Abstract
Aberrant signalling of ERBB family members plays an important role in tumorigenesis and in the escape from antitumour immunity in multiple malignancies. Molecular-targeted agents against these signalling pathways exhibit robust clinical efficacy, but patients inevitably experience acquired resistance to these molecular-targeted therapies. Although cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have shown durable antitumour response in a subset of the treated patients in multiple cancer types, clinical efficacy is limited in cancers harbouring activating gene alterations of ERBB family members. In particular, ICI treatment of patients with non-small cell lung cancers with epidermal growth factor receptor (EGFR) alterations and breast cancers with HER2 alterations failed to show clinical benefits, suggesting that EGFR and HER2 signalling may have an essential role in inhibiting antitumour immune responses. Here, we discuss the mechanisms by which the signalling of ERBB family members affects not only autonomous cancer hallmarks, such as uncontrolled cell proliferation, but also antitumour immune responses in the tumour microenvironment and the potential application of immune-genome precision medicine into immunotherapy and molecular-targeted therapy focusing on the signalling of ERBB family members.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Yarden, Y. & Pines, G. The ERBB network: at last, cancer therapy meets systems biology. Nat. Rev. Cancer 12, 553–563 (2012).
Roskoski, R. Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol. Res. 79, 34–74 (2014). Together with Yarden and Pines (2012), this paper presents comprehensive reviews of ERBB family signalling in various types of cancer.
Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011). This review summarizes an essential concept in the cancer immunology field regarding the interaction between the immune system and cancer cells during cancer development, ‘cancer immuno-editing’.
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015). Together with McGranahan et al. (2016), this paper shows the importance of the TMB in the efficacy of ICIs.
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).
Desrichard, A. et al. Tobacco smoking-associated alterations in the immune microenvironment of squamous cell carcinomas. J. Natl Cancer Inst. 110, 1386–1392 (2018).
Wang, S., Jia, M., He, Z. & Liu, X. S. APOBEC3B and APOBEC mutational signature as potential predictive markers for immunotherapy response in non-small cell lung cancer. Oncogene 37, 3924–3936 (2018).
Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).
Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852.e4 (2018).
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).
Sugiyama, E. et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci. Immunol. 5, eaav3937 (2020). This study shows an immunological role of EGFR signalling: aberrant EGFR signalling recruits Treg cells in the TME via chemokine production.
Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).
Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).
George, S. et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46, 197–204 (2017).
Kumagai, S. et al. An oncogenic alteration creates a microenvironment that promotes tumor progression by conferring a metabolic advantage to regulatory T cells. Immunity 53, 187–203.e8 (2020).
Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76, 999–1008 (2016).
Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).
Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
Gainor, J. F. et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin. Cancer Res. 22, 4585–4593 (2016).
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830.e14 (2018).
Prenzel, N., Fischer, O. M., Streit, S., Hart, S. & Ullrich, A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 8, 11–31 (2001).
Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127–137 (2001).
Holbro, T., Civenni, G. & Hynes, N. E. The ErbB receptors and their role in cancer progression. Exp. Cell Res. 284, 99–110 (2003).
Hynes, N. E. & MacDonald, G. ErbB receptors and signaling pathways in cancer. Curr. Opin. Cell Biol. 21, 177–184 (2009).
Shih, A. J., Telesco, S. E. & Radhakrishnan, R. Analysis of somatic mutations in cancer: molecular mechanisms of activation in the ErbB family of receptor tyrosine kinases. Cancers 3, 1195–1231 (2011).
Seshacharyulu, P. et al. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16, 15–31 (2012).
Balz, L. M. et al. The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination. J. Pathol. 227, 234–244 (2012).
Zhou, Q. et al. Activated human hydroxy-carboxylic acid receptor-3 signals to MAP kinase cascades via the PLC-dependent PKC and MMP-mediated EGFR pathways. Br. J. Pharmacol. 166, 1756–1773 (2012).
Fan, Q. W. et al. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell 24, 438–449 (2013).
Colomiere, M. et al. Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas. Br. J. Cancer 100, 134–144 (2009).
Tseng, P. C., Chen, C. L., Shan, Y. S. & Lin, C. F. An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells. Oncotarget 7, 15150–15160 (2016).
Matsuzaki, S. et al. Lysophosphatidic acid inhibits CC chemokine ligand 5/RANTES production by blocking IRF-1-mediated gene transcription in human bronchial epithelial cells. J. Immunol. 185, 4863–4872 (2010).
Van Raemdonck, K., Van den Steen, P. E., Liekens, S., Van Damme, J. & Struyf, S. CXCR3 ligands in disease and therapy. Cytokine Growth Factor Rev. 26, 311–327 (2015).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Jaiswal, B. S. et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23, 603–617 (2013).
Gilbertson, R. et al. Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma. Genes Chromosomes Cancer 31, 288–294 (2001).
Prickett, T. D. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat. Genet. 41, 1127–1132 (2009).
Pao, W. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).
Sugawa, N., Ekstrand, A. J., James, C. D. & Collins, V. P. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc. Natl Acad. Sci. USA 87, 8602–8606 (1990).
Shigematsu, H. & Gazdar, A. F. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int. J. Cancer 118, 257–262 (2006).
Hynes, N. E. & Schlange, T. Targeting ADAMS and ERBBs in lung cancer. Cancer Cell 10, 7–11 (2006).
Sharma, S. V. & Settleman, J. ErbBs in lung cancer. Exp. Cell Res. 315, 557–571 (2009).
Jorissen, R. N. et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res. 284, 31–53 (2003).
Motoyama, A. B., Hynes, N. E. & Lane, H. A. The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res. 62, 3151–3158 (2002).
Engelman, J. A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl Acad. Sci. USA 102, 3788–3793 (2005).
Holbro, T. et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl Acad. Sci. USA 100, 8933–8938 (2003).
Fujimoto, N. et al. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res. 65, 11478–11485 (2005).
Sundvall, M. et al. Role of ErbB4 in breast cancer. J. Mammary Gland Biol. Neoplasia 13, 259–268 (2008).
Gullick, W. J. c-erbB-4/HER4: friend or foe? J. Pathol. 200, 279–281 (2003).
Junttila, T. T., Sundvall, M., Maatta, J. A. & Elenius, K. Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. Trends Cardiovasc. Med. 10, 304–310 (2000).
Pao, W. & Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Cancer 10, 760–774 (2010).
Suda, K., Rivard, C. J., Mitsudomi, T. & Hirsch, F. R. Overcoming resistance to EGFR tyrosine kinase inhibitors in lung cancer, focusing on non-T790M mechanisms. Expert Rev. Anticancer Ther. 17, 779–786 (2017).
Rusnak, D. W. et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol. Cancer Ther. 1, 85–94 (2001).
O’Brien, N. A. et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol. Cancer Ther. 9, 1489–1502 (2010).
Konecny, G. E. et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 66, 1630–1639 (2006).
Xu, X. et al. HER2 reactivation through acquisition of the HER2 L755S mutation as a mechanism of acquired resistance to HER2-targeted therapy in HER2+ breast cancer. Clin. Cancer Res. 23, 5123–5134 (2017).
Douillard, J. Y. et al. FOLFOX4 with cetuximab vs. UFOX with cetuximab as first-line therapy in metastatic colorectal cancer: the randomized phase II FUTURE study. Clin. Colorectal Cancer 13, 14–26.e1 (2014).
Jonker, D. J. et al. Cetuximab for the treatment of colorectal cancer. N. Engl. J. Med. 357, 2040–2048 (2007).
Van Cutsem, E. et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007).
Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).
Matsuda, N. et al. Safety and efficacy of panitumumab plus neoadjuvant chemotherapy in patients with primary HER2-negative inflammatory breast cancer. JAMA Oncol. 4, 1207–1213 (2018).
Wang, X. et al. EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer. Oncotarget 8, 67904–67917 (2017).
Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).
Robert, N. et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J. Clin. Oncol. 24, 2786–2792 (2006).
Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).
Baselga, J. et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 366, 109–119 (2012).
Gianni, L. et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 25–32 (2012).
Schneeweiss, A. et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann. Oncol. 24, 2278–2284 (2013).
Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).
Ghosh, R. et al. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res. 71, 1871–1882 (2011).
Junttila, T. T. et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15, 429–440 (2009).
Molina, M. A. et al. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744–4749 (2001).
Yakes, F. M. et al. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 62, 4132–4141 (2002).
Agus, D. B. et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 (2002).
Garrett, J. T. et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc. Natl Acad. Sci. USA 108, 5021–5026 (2011).
Schoeberl, B. et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res. 70, 2485–2494 (2010).
Jacob, W., James, I., Hasmann, M. & Weisser, M. Clinical development of HER3-targeting monoclonal antibodies: perils and progress. Cancer Treat. Rev. 68, 111–123 (2018).
Haag, R. & Kratz, F. Polymer therapeutics: concepts and applications. Angew. Chem. Int. Ed. Engl. 45, 1198–1215 (2006).
Beck, A., Goetsch, L., Dumontet, C. & Corvaïa, N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).
Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).
Krop, I. E. et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 689–699 (2014).
Perez, E. A. et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J. Clin. Oncol. 35, 141–148 (2017).
Ogitani, Y. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22, 5097–5108 (2016).
Shitara, K. et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 382, 2419–2430 (2020).
Hashimoto, Y. et al. A novel HER3-targeting antibody–drug conjugate, U3-1402, exhibits potent therapeutic efficacy through the delivery of cytotoxic payload by efficient internalization. Clin. Cancer Res. 25, 7151–7161 (2019).
Wu, J. Y. et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin. Cancer Res. 14, 4877–4882 (2008).
Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).
Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).
Ou, S. I. et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer 108, 228–231 (2017).
Montagut, C. et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 18, 221–223 (2012).
Scaltriti, M. et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl Cancer Inst. 99, 628–638 (2007).
Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).
Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).
Brea, E. J. et al. Kinase regulation of human MHC class I molecule expression on cancer cells. Cancer Immunol. Res. 4, 936–947 (2016).
MacDonald, F. & Zaiss, D. M. W. The immune system’s contribution to the clinical efficacy of EGFR antagonist treatment. Front. Pharmacol. 8, 575 (2017).
Dong, Z. Y. et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology 6, e1356145 (2017).
Shi, Y. et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J. Thorac. Oncol. 9, 154–162 (2014).
Chen, Y. J. et al. Proteogenomics of non-smoking lung cancer in East Asia delineates molecular signatures of pathogenesis and progression. Cell 182, 226–244.e17 (2020). This study shows that EGFR-mutated NSCLCs present lower APOBEC mutational signatures than non-smoking EGFR-WT NSCLCs, which potentially lead to the relatively low TMB of EGFR-mutated NSCLCs.
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat. Rev. Clin. Oncol. 16, 356–371 (2019).
Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 21, 1346–1358 (2020).
Kamada, T. et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl Acad. Sci. USA 116, 9999–10008 (2019).
Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).
Spranger, S. et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013).
Akbay, E. A. et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 3, 1355–1363 (2013). This study shows that oncogenic EGFR signalling intrinsically elevates PDL1 expression and contributes to escape from antitumour immune responses in a preclinical model.
Ma, W. et al. EGFR signaling suppresses type 1 cytokine-induced T-cell attracting chemokine secretion in head and neck cancer. PloS ONE 13, e0203402 (2018).
Mascia, F., Mariani, V., Girolomoni, G. & Pastore, S. Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am. J. Pathol. 163, 303–312 (2003).
Lian, G. et al. Colon cancer cell secretes EGF to promote M2 polarization of TAM through EGFR/PI3K/AKT/mTOR pathway. Technol. Cancer Res. Treat. 18, 1533033819849068 (2019).
Yoshida, T. et al. Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clin. Cancer Res. 21, 642–651 (2015).
Cremasco, V. et al. FAP delineates heterogeneous and functionally divergent stromal cells in immune-excluded breast tumors. Cancer Immunol. Res. 6, 1472–1485 (2018).
Sakai, T. et al. Link between tumor-promoting fibrous microenvironment and an immunosuppressive microenvironment in stage I lung adenocarcinoma. Lung Cancer 126, 64–71 (2018).
Vantourout, P. et al. Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Sci. Transl. Med. 6, 231ra249 (2014).
Passarelli, A., Aieta, M., Sgambato, A. & Gridelli, C. Targeting immunometabolism mediated by CD73 pathway in EGFR-mutated non-small cell lung cancer: a new hope for overcoming immune resistance. Front. Immunol. 11, 1479 (2020).
Jia, Y. et al. EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: implications for combination therapies. Int. J. Cancer 145, 1432–1444 (2019).
Isomoto, K. et al. Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer. Clin. Cancer Res. 26, 2037–2046 (2020). In this study, CD8+ or FOXP3+ T cell densities in the TME are investigated with paired EGFR-mutated NSCLC tissue samples before and after acquired resistance to EGFR-TKI treatment.
Maynard, A. et al. Therapy-induced evolution of human lung cancer revealed by single-cell RNA sequencing. Cell 182, 1232–1251.e22 (2020). This study evaluates changes in immune phenotypes during EGFR-TKI treatment by single-cell RNA sequencing of TILs extracted from EGFR-mutated NSCLC tumour samples.
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med 3, 75ra26 (2011).
Witta, S. E. et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 66, 944–950 (2006).
Yao, Z. et al. TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc. Natl Acad. Sci. USA 107, 15535–15540 (2010).
Massagué, J. TGFβ in cancer. Cell 134, 215–230 (2008).
Tu, E., Chia, P. Z. & Chen, W. TGFβ in T cell biology and tumor immunity: angel or devil? Cytokine Growth Factor Rev. 25, 423–435 (2014).
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Chen, X. H. et al. TGF-β and EGF induced HLA-I downregulation is associated with epithelial–mesenchymal transition (EMT) through upregulation of snail in prostate cancer cells. Mol. Immunol. 65, 34–42 (2015).
Kudo-Saito, C., Shirako, H., Takeuchi, T. & Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15, 195–206 (2009).
Dongre, A. et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77, 3982–3989 (2017).
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).
Roche, P. A. & Furuta, K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat. Rev. Immunol. 15, 203–216 (2015).
DeSandro, A., Nagarajan, U. M. & Boss, J. M. The bare lymphocyte syndrome: molecular clues to the transcriptional regulation of major histocompatibility complex class II genes. Am. J. Hum. Genet. 65, 279–286 (1999).
Accolla, R. S. et al. Boosting the MHC class II-restricted tumor antigen presentation to CD4+ T helper cells: a critical issue for triggering protective immunity and re-orienting the tumor microenvironment toward an anti-tumor state. Front. Oncol. 4, 32 (2014).
Garrido, F., Cabrera, T. & Aptsiauri, N. “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int. J. Cancer 127, 249–256 (2010).
Kotekar, A. S., Weissman, J. D., Gegonne, A., Cohen, H. & Singer, D. S. Histone modifications, but not nucleosomal positioning, correlate with major histocompatibility complex class I promoter activity in different tissues in vivo. Mol. Cell. Biol. 28, 7323–7336 (2008).
van den Elsen, P. J. Expression regulation of major histocompatibility complex class I and class II encoding genes. Front. Immunol. 2, 48 (2011).
Seliger, B. Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol. Immunother. 57, 1719–1726 (2008).
Hastings, K. T. GILT: shaping the MHC class II-restricted peptidome and CD4+ T cell-mediated immunity. Front. Immunol. 4, 429 (2013).
Kim, R., Emi, M., Tanabe, K. & Arihiro, K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 66, 5527–5536 (2006).
Marincola, F. M., Jaffee, E. M., Hicklin, D. J. & Ferrone, S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv. Immunol. 74, 181–273 (2000).
Seliger, B. Different regulation of MHC class I antigen processing components in human tumors. J. Immunotoxicol. 5, 361–367 (2008).
Seliger, B. The link between MHC class I abnormalities of tumors, oncogenes, tumor suppressor genes, and transcription factors. J. Immunotoxicol. 11, 308–310 (2014).
van der Burg, S. H., Arens, R., Ossendorp, F., van Hall, T. & Melief, C. J. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat. Rev. Cancer 16, 219–233 (2016).
Schreiber, A. B., Schlessinger, J. & Edidin, M. Interaction between major histocompatibility complex antigens and epidermal growth factor receptors on human cells. J. Cell Biol. 98, 725–731 (1984).
Sporn, M. B. & Roberts, A. B. Autocrine growth factors and cancer. Nature 313, 745–747 (1985).
Lahat, N., Sheinfeld, M., Sobel, E., Kinarty, A. & Kraiem, Z. Divergent effects of cytokines on human leukocyte antigen-DR antigen expression of neoplastic and non-neoplastic human thyroid cells. Cancer 69, 1799–1807 (1992).
Pollack, B. P. EGFR inhibitors, MHC expression and immune responses: can EGFR inhibitors be used as immune response modifiers? Oncoimmunology 1, 71–74 (2012).
Chandrasekaran, S. et al. Phosphoinositide 3-kinase signaling can modulate MHC class I and II expression. Mol. Cancer Res. 17, 2395–2409 (2019).
Marijt, K. A. et al. Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling. J. Immunother. Cancer 7, 152 (2019).
Sivaram, N. et al. Tumor-intrinsic PIK3CA represses tumor immunogenecity in a model of pancreatic cancer. J. Clin. Invest. 129, 3264–3276 (2019).
Watanabe, S. et al. Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer. Cancer Sci. 110, 52–60 (2019). This study shows that aberrant EGFR signalling inhibits MHC class I expression.
Mimura, K. et al. The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer. J. Immunol. 191, 6261–6272 (2013).
Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl. Med. 7, 279ra241 (2015).
Sabbatino, F. et al. Antitumor activity of BRAF inhibitor and IFNα combination in BRAF-mutant melanoma. J. Natl Cancer Inst. 108, djv435 (2016).
Whipple, C. A. et al. The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells. Melanoma Res. 26, 223–235 (2016).
Sapkota, B., Hill, C. E. & Pollack, B. P. Vemurafenib enhances MHC induction in BRAF(V600E) homozygous melanoma cells. Oncoimmunology 2, e22890 (2013).
Pollack, B. P., Sapkota, B. & Cartee, T. V. Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin. Cancer Res. 17, 4400–4413 (2011).
Kumai, T. et al. EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. Br. J.Cancer 109, 2155–2166 (2013).
Kumai, T. et al. Targeting HER-3 to elicit antitumor helper T cells against head and neck squamous cell carcinoma. Sci. Rep. 5, 16280 (2015).
Okita, R. et al. Contrasting effects of the cytotoxic anticancer drug gemcitabine and the EGFR tyrosine kinase inhibitor gefitinib on NK cell-mediated cytotoxicity via regulation of NKG2D ligand in non-small-cell lung cancer cells. PloS ONE 10, e0139809 (2015).
Gao, L. et al. Tumor-derived exosomes antagonize innate antiviral immunity. Nat. Immunol. 19, 233–245 (2018).
Wintterle, S. et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 63, 7462–7467 (2003).
Budczies, J. et al. Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) — associations with gene expression, mutational load, and survival. Genes Chromosomes Cancer 55, 626–639 (2016).
Kataoka, K. et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 534, 402–406 (2016).
Lastwika, K. J. et al. Control of PD-L1 expression by oncogenic activation of the AKT–mTOR pathway in non-small cell lung cancer. Cancer Res. 76, 227–238 (2016).
Chen, N. et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J. Thorac. Oncol. 10, 910–923 (2015).
Zhang, N. et al. The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. Int. J. Oncol. 49, 1360–1368 (2016).
Gao, S. P. et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856 (2007).
Takada, K. et al. PD-L1 expression according to the EGFR status in primary lung adenocarcinoma. Lung Cancer 116, 1–6 (2018).
Lee, J. et al. PD-L1 expression in ROS1-rearranged non-small cell lung cancer: a study using simultaneous genotypic screening of EGFR, ALK, and ROS1. Thorac. Cancer 10, 103–110 (2019).
Heigener, D. F. & Reck, M. Impact of PD-L1 expression in EGFR-positive NSCLC? The answer remains the same. J. Thorac. Oncol. 13, 1060–1061 (2018).
Ji, M. et al. PD-1/PD-L1 expression in non-small-cell lung cancer and its correlation with EGFR/KRAS mutations. Cancer Biol. Ther. 17, 407–413 (2016).
Li, J. et al. A systematic and genome-wide correlation meta-analysis of PD-L1 expression and targetable NSCLC driver genes. J. Thorac. Dis. 9, 2560–2571 (2017).
Han, J. J. et al. Change in PD-L1 expression after acquiring resistance to gefitinib in EGFR-mutant non-small-cell lung cancer. Clin. Lung Cancer 17, 263–270.e2 (2016).
Shibahara, D. et al. Intrinsic and extrinsic regulation of PD-L2 expression in oncogene-driven non-small cell lung cancer. J. Thorac. Oncol. 13, 926–937 (2018).
Zhao, R. et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc. Natl Acad. Sci. USA 110, 9879–9884 (2013).
Cheng, H. et al. HHLA2, a new immune checkpoint member of the B7 family, is widely expressed in human lung cancer and associated with EGFR mutational status. Clin. Cancer Res. 23, 825–832 (2017).
Jin, D. et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70, 2245–2255 (2010).
Ring, S., Enk, A. H. & Mahnke, K. ATP activates regulatory T cells in vivo during contact hypersensitivity reactions. J. Immunol. 184, 3408–3416 (2010).
Morello, S. & Miele, L. Targeting the adenosine A2b receptor in the tumor microenvironment overcomes local immunosuppression by myeloid-derived suppressor cells. Oncoimmunology 3, e27989 (2014).
Zarek, P. E. et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111, 251–259 (2008).
Marteau, F. et al. Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells. Blood 106, 3860–3866 (2005).
Goto, T., Herberman, R. B., Maluish, A. & Strong, D. M. Cyclic AMP as a mediator of prostaglandin E-induced suppression of human natural killer cell activity. J. Immunol. 130, 1350–1355 (1983).
Nowak, M. et al. The A2aR adenosine receptor controls cytokine production in iNKT cells. Eur. J. Immunol. 40, 682–687 (2010).
Panther, E. et al. Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101, 3985–3990 (2003).
Panther, E. et al. Expression and function of adenosine receptors in human dendritic cells. FASEB J. 15, 1963–1970 (2001).
Zhang, H. et al. Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3′,5′-monophosphate and phosphatases. J. Immunol. 173, 932–944 (2004).
Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).
Ohta, A. et al. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J. Immunol. 183, 5487–5493 (2009).
Park, L. C. et al. Immunologic and clinical implications of CD73 expression in non-small cell lung cancer (NSCLC). J. Clin. Oncol. 36, 12050–12050 (2018).
Sidders, B. et al. Adenosine signaling is prognostic for cancer outcome and has predictive utility for immunotherapeutic response. Clin.Cancer Res. 26, 2176–2187 (2020). This study shows that high levels of baseline tumour adenosine signalling are associated with resistance to ICIs in various types of cancer.
Streicher, K. et al. Increased CD73 and reduced IFNG signature expression in relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC. J. Clin. Oncol. 35, 1150 (2017).
Wang, C., Yu, X. & Wang, W. A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer. Medicine 95, e5539 (2016).
Khan, M. et al. Comparative analysis of immune checkpoint inhibitors and chemotherapy in the treatment of advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. Medicine 97, e11936 (2018).
Lee, C. K. et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 4, 210–216 (2018). This meta-analysis fails to show overall survival benefit of ICIs for patients with EGFR-mutated NSCLCs in second-line therapy.
Lee, C. K. et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer — a meta-analysis. J. Thorac. Oncol. 12, 403–407 (2017).
Sun, L. et al. Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis. Sci. Rep. 10, 2083 (2020).
Hastings, K. et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann. Oncol. 30, 1311–1320 (2019). This study shows that the clinical efficacy of ICIs in EGFR-mutated NSCLCs is variable depending on the types of EGFR mutations.
Offin, M. et al. Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers. Clin. Cancer Res. 25, 1063–1069 (2019).
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).
Dogan, S. et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin. Cancer Res. 18, 6169–6177 (2012).
Lee, B., Lee, T., Lee, S. H., Choi, Y. L. & Han, J. Clinicopathologic characteristics of EGFR, KRAS, and ALK alterations in 6,595 lung cancers. Oncotarget 7, 23874–23884 (2016).
Haratani, K. et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann. Oncol. 28, 1532–1539 (2017).
Hata, A. et al. Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer. Lung Cancer 111, 182–189 (2017).
Yamada, T. et al. Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer. Cancer Med. 8, 1521–1529 (2019).
Mok, T. S. et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).
Evans, M. et al. Large-scale EGFR mutation testing in clinical practice: analysis of a series of 18,920 non-small cell lung cancer cases. Pathol. Oncol. Res. 25, 1401–1409 (2019).
Lohinai, Z. et al. Distinct epidemiology and clinical consequence of classic versus rare EGFR mutations in lung adenocarcinoma. J. Thorac. Oncol. 10, 738–746 (2015).
Sheng, Q. et al. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17, 298–310 (2010).
Chen, K. et al. PD-L1 expression and T cells infiltration in patients with uncommon EGFR-mutant non-small cell lung cancer and the response to immunotherapy. Lung Cancer 142, 98–105 (2020).
Loi, S. et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J. Clin. Oncol. 31, 860–867 (2013).
Yamaguchi, R. et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum. Pathol. 43, 1688–1694 (2012).
Ali, H. R. et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann. Oncol. 25, 1536–1543 (2014).
Todorović-Raković, N. & Milovanović, J. Interleukin-8 in breast cancer progression. J. Interferon Cytokine Res. 33, 563–570 (2013).
Paplomata, E. & O’Regan, R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther. Adv. Med. Oncol. 6, 154–166 (2014).
Yuen, K. C. et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat. Med. 26, 693–698 (2020).
Wu, S. et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat. Cell Biol. 21, 1027–1040 (2019). This study shows that HER2 amplification induces loss of phosphorylation of TBK1 and attenuates STING signalling, resulting in the impairment of the interferon response and antitumour immune responses.
Herrmann, F. et al. HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway. Cancer Res. 64, 215–220 (2004).
Mortenson, E. D., Park, S., Jiang, Z., Wang, S. & Fu, Y. X. Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells. Clin. Cancer Res. 19, 1476–1486 (2013).
Choudhury, A. et al. Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines. Int. J. Cancer 108, 71–77 (2004).
Burr, M. L. et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature 549, 101–105 (2017).
Li, C. W. et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat. Commun. 7, 12632 (2016).
Mezzadra, R. et al. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature 549, 106–110 (2017).
Li, C. W. et al. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell 33, 187–201.e10 (2018).
Kubota, Y., et al. The impact of molecular subtype on efficacy of chemotherapy and checkpoint inhibition in advanced gastric cancer. Clin. Cancer Res. 26, 3784–3790 (2020). This study shows that PD1 blockade therapies show limited antitumour efficacy in gastric cancers with HER2 amplification.
Dirix, L. Y. et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res. Treat. 167, 671–686 (2018).
Lanaya, H. et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat. Cell Biol. 16, 972–977 (2014).
Srivatsa, S. et al. EGFR in tumor-associated myeloid cells promotes development of colorectal cancer in mice and associates with outcomes of patients. Gastroenterology 153, 178–190.e10 (2017).
Nabeshima, A. et al. Tumour-associated macrophages correlate with poor prognosis in myxoid liposarcoma and promote cell motility and invasion via the HB–EGF–EGFR–PI3K/Akt pathways. Br. J.Cancer 112, 547–555 (2015).
Zaiss, D. M. et al. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity 38, 275–284 (2013).
Green, J. A., Arpaia, N., Schizas, M., Dobrin, A. & Rudensky, A. Y. A nonimmune function of T cells in promoting lung tumor progression. J. Exp. Med. 214, 3565–3575 (2017).
Gourd, K. AstraZeneca halts two lung cancer drug trials. Lancet Respir. Med. 3, 926 (2015).
Gettinger, S. et al. Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC. J. Thorac. Oncol. 13, 1363–1372 (2018).
Gong, K. et al. EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer. Nat. Cancer 1, 394–409 (2020). This study shows that EGFR-TKIs upregulate interferons not only in EGFR-mutated human cancer cell lines but also in EGFR-WT human cancer cell lines.
Saito, H. et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 20, 625–635 (2019).
Tada, Y. et al. Targeting VEGFR2 with ramucirumab strongly impacts effector/activated regulatory T cells and CD8+ T cells in the tumor microenvironment. J. Immunother. Cancer 6, 106 (2018).
Koinis, F. et al. Effect of first-line treatment on myeloid-derived suppressor cells’ subpopulations in the peripheral blood of patients with non-small cell lung cancer. J. Thorac. Oncol. 11, 1263–1272 (2016).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).
Reck, M. et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir. Med. 7, 387–401 (2019). This clinical trial shows the additional clinical benefit of anti-PDL1 mAb with chemotherapy plus anti-VEGF mAb even in EGFR-mutated NSCLCs.
Beavis, P. A. et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor t-cell responses. Cancer Immunol. Res. 3, 506–517 (2015).
Allard, B., Pommey, S., Smyth, M. J. & Stagg, J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19, 5626–5635 (2013).
Ciardiello, F. & Tortora, G. EGFR antagonists in cancer treatment. N. Engl. J Med. 358, 1160–1174 (2008).
Trivedi, S. et al. Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients. Clin. Cancer Res. 22, 5229–5237 (2016).
Trotta, A. M. et al. Prospective evaluation of cetuximab-mediated antibody-dependent cell cytotoxicity in metastatic colorectal cancer patients predicts treatment efficacy. Cancer Immunol. Res. 4, 366–374 (2016).
Pozzi, C. et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 22, 624–631 (2016).
Concha-Benavente, F. et al. PD-L1 mediates dysfunction in activated PD-1+ NK cells in head and neck cancer patients. Cancer Immunol. Res. 6, 1548–1560 (2018).
Varadan, V. et al. Immune signatures following single dose trastuzumab predict pathologic response to preoperativetrastuzumab and chemotherapy in HER2-positive early breast cancer. Clin. Cancer Res. 22, 3249–3259 (2016).
Chaganty, B. K. R. et al. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion. Cancer Lett. 430, 47–56 (2018).
Loi, S. et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 20, 371–382 (2019).
Janjigian, Y. Y. et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol. 21, 821–831 (2020). Together with Loi et al. (2019), this paper shows promising outcomes in combination therapies of anti-HER2 mAbs with ICIs in breast cancer and gastric cancer with HER2 amplification.
Junttila, T. T., Li, G., Parsons, K., Phillips, G. L. & Sliwkowski, M. X. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat. 128, 347–356 (2011).
Birrer, M. J., Moore, K. N., Betella, I. & Bates, R. C. Antibody–drug conjugate-based therapeutics: state of the science. J. Natl Cancer Inst. 111, 538–549 (2019).
Müller, P. et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl. Med. 7, 315ra188 (2015).
Iwata, T. N. et al. A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol. Cancer Ther. 17, 1494–1503 (2018).
Haratani, K. et al. U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation. J. Clin. Invest. 130, 374–388 (2020). Together with Müller et al. (2015) and Iwata et al. (2018), this paper shows that ERBB-targeted ADCs augment antitumour effects of PD1 blockade in preclinical models.
Kawazoe, A. et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 21, 1057–1065 (2020).
Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).
Hanker, A. B. et al. An acquired HER2(T798I) gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer. Cancer Discov. 7, 575–585 (2017).
Kosaka, T. et al. Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors. Cancer Res. 77, 2712–2721 (2017).
Nagy, P. et al. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res. 65, 473–482 (2005).
Pályi-Krekk, Z. et al. Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer. Eur. J. Cancer 43, 2423–2433 (2007).
Ghatak, S., Misra, S. & Toole, B. P. Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J. Biol. Chem. 277, 38013–38020 (2002).
Ohashi, K. et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc. Natl Acad. Sci. USA 109, E2127–E2133 (2012).
Ercan, D. et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2, 934–947 (2012).
Diaz, L. A. Jr et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).
Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).
de Bruin, E. C. et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 4, 606–619 (2014).
Tricker, E. M. et al. Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov. 5, 960–971 (2015).
Ho, C. C. et al. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J. Thorac. Oncol. 12, 567–572 (2017).
Chakrabarty, A. et al. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29, 5193–5203 (2010).
Eichhorn, P. J. et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221–9230 (2008).
Serra, V. et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68, 8022–8030 (2008).
Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).
Dave, B. et al. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J. Clin. Oncol. 29, 166–173 (2011).
Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004).
Engelman, J. A. et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J. Clin. Invest. 116, 2695–2706 (2006).
Sos, M. L. et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 69, 3256–3261 (2009).
Li, G. et al. Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells. Mol. Cancer Ther. 17, 1441–1453 (2018).
Blakely, C. M. et al. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 11, 98–110 (2015).
Gao, S. P. et al. JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci. Signal. 9, ra33 (2016).
Chaib, I. et al. Co-activation of STAT3 and YES-associated protein 1 (YAP1) pathway in EGFR-mutant NSCLC. J. Natl Cancer Inst. 109, djx014 (2017).
Shou, J. et al. Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3. Cancer Lett. 379, 124–133 (2016).
Kanda, R. et al. Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 73, 6243–6253 (2013).
Yoshida, T. et al. Effects of Src inhibitors on cell growth and epidermal growth factor receptor and MET signaling in gefitinib-resistant non-small cell lung cancer cells with acquired MET amplification. Cancer Sci. 101, 167–172 (2010).
Takezawa, K. et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2, 922–933 (2012).
Lee-Hoeflich, S. T. et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 68, 5878–5887 (2008).
Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).
Xia, W. et al. An heregulin–EGFR–HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res. 15, R85 (2013).
Cortot, A. B. et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 73, 834–843 (2013).
Guix, M. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest. 118, 2609–2619 (2008).
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104, 20932–20937 (2007).
Minuti, G. et al. Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer. Br. J. Cancer 107, 793–799 (2012).
Yano, S. et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479–9487 (2008).
Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).
Byers, L. A. et al. An epithelial–mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 19, 279–290 (2013).
Faber, A. C. et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov. 1, 352–365 (2011).
Ng, K. P. et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat. Med. 18, 521–528 (2012).
Costa, C. et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin. Cancer Res. 20, 2001–2010 (2014).
Lee, J. E. et al. Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance. Biochem. Biophys. Res. Commun. 474, 154–160 (2016).
Nahta, R., Takahashi, T., Ueno, N. T., Hung, M. C. & Esteva, F. J. p27kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 64, 3981–3986 (2004).
Niederst, M. J. et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6, 6377 (2015).
Musolino, A. et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J. Clin. Oncol. 26, 1789–1796 (2008).
Kovtun, Y. V. et al. Antibody–maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res. 70, 2528–2537 (2010).
Sung, M. et al. Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1). Mol. Cancer Ther. 17, 243–253 (2018).
Smith, L. M., Nesterova, A., Alley, S. C., Torgov, M. Y. & Carter, P. J. Potent cytotoxicity of an auristatin-containing antibody–drug conjugate targeting melanoma cells expressing melanotransferrin/p97. Mol. Cancer Ther. 5, 1474–1482 (2006).
Kinneer, K. et al. SLC46A3 as a potential predictive biomarker for antibody-drug conjugates bearing noncleavable linked maytansinoid and pyrrolobenzodiazepine warheads. Clin. Cancer Res. 24, 6570–6582 (2018).
Oxnard, G. R. et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann. Oncol. 31, 507–516 (2020).
Yang, J. C. et al. Pembrolizumab in combination with erlotinib or gefitinib as first-line therapy for advanced NSCLC with sensitizing EGFR mutation. J. Thorac. Oncol. 14, 553–559 (2019).
Yang, J. C. et al. Osimertinib plus durvalumab versus osimertinib monotherapy in EGFR T790M-positive NSCLC following previous EGFR TKI therapy: CAURAL brief report. J. Thorac. Oncol. 14, 933–939 (2019).
Emens, L. et al. Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC) [abstract PD3-01]. Cancer Res. 79 (Suppl. 4), PD3-01 (2019).
Casalini, P., Iorio, M. V., Galmozzi, E. & Menard, S. Role of HER receptors family in development and differentiation. J. Cell. Physiol. 200, 343–350 (2004).
Roskoski, R. Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem. Biophys. Res. Commun. 319, 1–11 (2004).
Hynes, N. E., Horsch, K., Olayioye, M. A. & Badache, A. The ErbB receptor tyrosine family as signal integrators. Endocr. Relat. Cancer 8, 151–159 (2001).
Shi, F., Telesco, S. E., Liu, Y., Radhakrishnan, R. & Lemmon, M. A. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc. Natl Acad. Sci. USA 107, 7692–7697 (2010).
Acknowledgements
This study was supported by Grants-in-Aid for Scientific Research grant no. 17H06162 (to H.N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Projects for Cancer Research by Therapeutic Evolution (P-CREATE; no. 16cm0106301h0001 to H.N. and no. 19cm0106335h0002 and 19cm0106310h0004 to S.Ko.), the Development of Technology for Patient Stratification Biomarker Discovery grant (no. 19ae0101074s0401 to H.N.) from the Japan Agency for Medical Research and Development (AMED), and the National Cancer Center Research and Development Fund (no. 28-A-7 and 31-A-7 to H.N.).
Author information
Authors and Affiliations
Contributions
All authors contributed to each stage of the preparation of this manuscript.
Corresponding author
Ethics declarations
Competing interests
S.Ko. received research funding from Ono Pharmaceutical and Bristol-Myers Squibb outside this study. H.N. received honoraria and research funding from Ono Pharmaceutical, Chugai Pharmaceutical, MSD and Bristol-Myers Squibb, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma and BD Japan outside this study. All other authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Cancer thanks B. Pollack, F. Skoulidis and N. Ueno for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Neoantigens
-
Antigens derived from gene alterations in tumour cells. As they are recognized as foreign bodies by the immune system, strong immune responses are generally induced.
- Antibody-dependent cellular cytotoxicity
-
(ADCC). When antibodies bind to the target cells, especially cancer cells, immune cells such as macrophages and natural killer cells are attracted. These attracted immune cells possess activating Fc receptors that recognize the Fc region of the antibody, and kill the targeted cells to which the antibody binds through releasing cytotoxic molecules.
- NKT cells
-
A type of T cells that also possess the characteristics of natural killer cells. The T cell receptors of natural killer T (NKT) cells recognize glycolipids presented on CD1d molecules as antigens.
Rights and permissions
About this article
Cite this article
Kumagai, S., Koyama, S. & Nishikawa, H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer 21, 181–197 (2021). https://doi.org/10.1038/s41568-020-00322-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41568-020-00322-0
This article is cited by
-
Crosstalk between KDEL receptor and EGF receptor mediates cell proliferation and migration via STAT3 signaling
Cell Communication and Signaling (2024)
-
Novel T cell exhaustion gene signature to predict prognosis and immunotherapy response in thyroid carcinoma from integrated RNA-sequencing analysis
Scientific Reports (2024)
-
Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine
Nature Reviews Clinical Oncology (2024)
-
SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs
Acta Pharmacologica Sinica (2024)
-
Myeloid cell-targeted therapies for solid tumours
Nature Reviews Immunology (2023)
