Resistance to cancer therapy remains a major challenge in clinical oncology. Although the initial treatment phase is often successful, eventual resistance, characterized by tumour relapse or spread, is discouraging. The majority of studies devoted to investigating the basis of resistance have focused on tumour-related changes that contribute to therapy resistance and tumour aggressiveness. However, over the last decade, the diverse roles of various host cells in promoting therapy resistance have become more appreciated. A growing body of evidence demonstrates that cancer therapy can induce host-mediated local and systemic responses, many of which shift the delicate balance within the tumour microenvironment, ultimately facilitating or supporting tumour progression. In this Review, recent advances in understanding how the host response to different cancer therapies may promote therapy resistance are discussed, with a focus on therapy-induced immunological, angiogenic and metastatic effects. Also summarized is the potential of evaluating the host response to cancer therapy in an era of precision medicine in oncology.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kerbel, R. S. Tumor angiogenesis. N. Engl. J. Med. 358, 2039–2049 (2008).
Yamaguchi, H. et al. Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells. PLOS ONE 9, e85485 (2014).
Nadir, Y. & Brenner, B. Heparanase multiple effects in cancer. Thromb Res. 133, S90–S94 (2014).
Shaked, Y. & Voest, E. E. Bone marrow derived cells in tumor angiogenesis and growth: are they the good, the bad or the evil? Biochim. Biophys. Acta 1796, 1–4 (2009).
Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).
Powell, D. R. & Huttenlocher, A. Neutrophils in the tumor microenvironment. Trends Immunol. 37, 41–52 (2016).
Maltby, S., Khazaie, K. & McNagny, K. M. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim. Biophys. Acta. 1796, 19–26 (2009).
Nieman, K. M., Romero, I. L., Van Houten, B. & Lengyel, E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta 1831, 1533–1541 (2013).
Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D. & Lopez-Soto, A. The hallmarks of successful anticancer immunotherapy. Sci. Transl Med. 10, eaat7807 (2018).
Jayson, G. C., Kerbel, R., Ellis, L. M. & Harris, A. L. Antiangiogenic therapy in oncology: current status and future directions. Lancet 388, 518–529 (2016).
Groenendijk, F. H. & Bernards, R. Drug resistance to targeted therapies: deja vu all over again. Mol. Oncol. 8, 1067–1083 (2014).
Mansoori, B., Mohammadi, A., Davudian, S., Shirjang, S. & Baradaran, B. The different mechanisms of cancer drug resistance: a brief review. Adv. Pharm. Bull. 7, 339–348 (2017).
Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714–726 (2013).
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012). This major review focuses on the role of host cells within the TME, which contribute to the hallmarks of cancer.
Shaked, Y. Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Nat. Rev. Clin. Oncol. 13, 611–626 (2016). This is perhaps the first extensive review on the pro-tumorigenic and anti-tumorigenic role of anticancer therapies and their impact on tumour regrowth and resistance to therapy, highlighting the balance between the action of and the reaction to anticancer drugs.
Daenen, L. G. et al. Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies. Oncogene 33, 1341–1347 (2014).
Kerbel, R. S. & Shaked, Y. Therapy-activated stromal cells can dictate tumor fate. J. Exp. Med. 213, 2831–2833 (2016).
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).
Zagozdzon, R. & Golab, J. Immunomodulation by anticancer chemotherapy: more is not always better (review). Int. J. Oncol. 18, 417–424 (2001).
Karagiannis, G. S., Condeelis, J. S. & Oktay, M. H. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin. Exp. Metastasis 35, 269–284 (2018).
Blyth, B. J., Cole, A. J., MacManus, M. P. & Martin, O. A. Radiation therapy-induced metastasis: radiobiology and clinical implications. Clin. Exp. Metastasis 35, 223–236 (2018).
Meeren, A. V., Bertho, J. M., Vandamme, M. & Gaugler, M. H. Ionizing radiation enhances IL-6 and IL-8 production by human endothelial cells. Mediators Inflamm. 6, 185–193 (1997).
Toste, P. A. et al. Chemotherapy-induced inflammatory gene signature and protumorigenic phenotype in pancreatic CAFs via stress-associated MAPK. Mol. Cancer Res. 14, 437–447 (2016).
Fisher, D. T., Appenheimer, M. M. & Evans, S. S. The two faces of IL-6 in the tumor microenvironment. Semin. Immunol. 26, 38–47 (2014).
David, J. M., Dominguez, C., Hamilton, D. H. & Palena, C. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines 4, E22 (2016).
Rialdi, A. et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352, aad7993 (2016).
Zhang, F. et al. Specific decrease in B-cell-derived extracellular vesicles enhances post-chemotherapeutic CD8+ T cell responses. Immunity 50, 738–750.e7 (2019).
Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499–4506 (2009).
Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013). This study describes the immunomodulatory effects of several chemotherapeutic drugs. For example, chemotherapy-activated MDSCs secrete immunomodulatory molecules that eventually contribute to tumour growth.
Takeuchi, S. et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 75, 2629–2640 (2015).
Hasnis, E. et al. Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. Neoplasia 16, 501–510 (2014).
Kozin, S. V. et al. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 70, 5679–5685 (2010).
Sugimura, K. et al. High infiltration of tumor-associated macrophages is associated with a poor response to chemotherapy and poor prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer. J. Surg. Oncol. 111, 752–759 (2015).
Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588–602.e10 (2019).
Mantovani, A. & Allavena, P. The interaction of anticancer therapies with tumor-associated macrophages. J. Exp. Med. 212, 435–445 (2015).
Sanchez, L. R. et al. The emerging roles of macrophages in cancer metastasis and response to chemotherapy. J. Leukoc. Biol. 106, 259–274 (2019).
Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).
Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).
De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).
Gallin, E. K. & Green, S. W. Exposure to gamma-irradiation increases phorbol myristate acetate-induced H2O2 production in human macrophages. Blood 70, 694–701 (1987).
Milas, L., Wike, J., Hunter, N., Volpe, J. & Basic, I. Macrophage content of murine sarcomas and carcinomas: associations with tumor growth parameters and tumor radiocurability. Cancer Res. 47, 1069–1075 (1987).
Middleton, J. D., Stover, D. G. & Hai, T. Chemotherapy-exacerbated breast cancer metastasis: a paradox explainable by dysregulated adaptive-response. Int. J. Mol. Sci. 19, E3333 (2018).
Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).
Oelmann, E. et al. Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin/Reed–Sternberg cells. Blood 99, 258–267 (2002).
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Crohns, M. et al. Cytokines in bronchoalveolar lavage fluid and serum of lung cancer patients during radiotherapy—association of interleukin-8 and VEGF with survival. Cytokine 50, 30–36 (2010).
Xu, J. et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 73, 2782–2794 (2013).
Nguyen, D. H. et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 19, 640–651 (2011).
Wrzesinski, S. H., Wan, Y. Y. & Flavell, R. A. Transforming growth factor-β and the immune response: implications for anticancer therapy. Clin. Cancer Res. 13, 5262–5270 (2007).
Mutsaers, A. J. et al. Dose-dependent increases in circulating TGF-α and other EGFR ligands act as pharmacodynamic markers for optimal biological dosing of cetuximab and are tumor independent. Clin. Cancer Res. 15, 2397–2405 (2009).
Loupakis, F. et al. EGFR ligands as pharmacodynamic biomarkers in metastatic colorectal cancer patients treated with cetuximab and irinotecan. Target Oncol. 9, 205–214 (2014).
Asimakopoulos, F. et al. Macrophages in multiple myeloma: emerging concepts and therapeutic implications. Leukemia Lymphoma 54, 2112–2121 (2013).
Beyar-Katz, O. et al. Bortezomib-induced pro-inflammatory macrophages as a potential factor limiting anti-tumour efficacy. J. Pathol. 239, 262–273 (2016).
Zhang, W. et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin. Cancer Res. 16, 3420–3430 (2010).
Roberts, P. J. & Der, C. J. Targeting the Raf–MEK–ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26, 3291–3310 (2007).
Sharkey, M. S., Lizee, G., Gonzales, M. I., Patel, S. & Topalian, S. L. CD4+ T-cell recognition of mutated B-RAF in melanoma patients harboring the V599E mutation. Cancer Res. 64, 1595–1599 (2004).
Wang, T. et al. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin. Cancer Res. 21, 1652–1664 (2015).
Demicheli, R., Retsky, M. W., Hrushesky, W. J., Baum, M. & Gukas, I. D. The effects of surgery on tumor growth: a century of investigations. Ann. Oncol. 19, 1821–1828 (2008). This review is among several other studies and reviews summarizing the long history leading up to the concept of surgery-induced metastasis. The review focuses on tumour dormancy, circulating tumour cells and clinical studies that support this concept.
Shakhar, G. & Ben-Eliyahu, S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann. Surg. Oncol. 10, 972–992 (2003).
Crucitti, A. et al. Laparoscopic surgery for colorectal cancer is not associated with an increase in the circulating levels of several inflammation-related factors. Cancer Biol. Ther. 16, 671–677 (2015).
Alieva, M., van Rheenen, J. & Broekman, M. L. D. Potential impact of invasive surgical procedures on primary tumor growth and metastasis. Clin. Exp. Metastasis 35, 319–331 (2018).
Predina, J. et al. Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc. Natl Acad. Sci. USA 110, E415–E424 (2013).
Sammour, T., Kahokehr, A., Chan, S., Booth, R. J. & Hill, A. G. The humoral response after laparoscopic versus open colorectal surgery: a meta-analysis. J. Surg. Res. 164, 28–37 (2010).
Tartter, P. I., Steinberg, B., Barron, D. M. & Martinelli, G. The prognostic significance of natural killer cytotoxicity in patients with colorectal cancer. Arch. Surg. 122, 1264–1268 (1987).
Fujisawa, T. & Yamaguchi, Y. Autologous tumor killing activity as a prognostic factor in primary resected nonsmall cell carcinoma of the lung. Cancer 79, 474–481 (1997).
Shaashua, L. et al. Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin. Cancer Res. 23, 4651–4661 (2017).
Horowitz, M., Neeman, E., Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213–226 (2015).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat. Rev. Cancer 8, 579–591 (2008).
Shaked, Y. et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14, 263–273 (2008).
Alishekevitz, D. et al. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 17, 1344–1356 (2016).
Shaked, Y. et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313, 1785–1787 (2006). This study is perhaps one of the first demonstrating how therapy induces a systemic angiogenic response that, in turn, contributes to tumour regrowth. In response to VDAs, endothelial precursor cells rapidly home to the treated tumour site, supporting angiogenesis and subsequent tumour regrowth.
Natori, T. et al. G-CSF stimulates angiogenesis and promotes tumor growth: potential contribution of bone marrow-derived endothelial progenitor cells. Biochem. Biophys. Res. Commun. 297, 1058–1061 (2002).
Furstenberger, G. et al. Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br. J. Cancer. 94, 524–531 (2006).
Okazaki, T. et al. Granulocyte colony-stimulating factor promotes tumor angiogenesis via increasing circulating endothelial progenitor cells and Gr1+CD11b+ cells in cancer animal models. Int. Immunol. 18, 1–9 (2006).
Farace, F., Massard, C., Borghi, E., Bidart, J. M. & Soria, J. C. Vascular disrupting therapy-induced mobilization of circulating endothelial progenitor cells. Ann. Oncol. 18, 1421–1422 (2007).
Taylor, M. et al. Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells. Cancer Discov. 2, 434–449 (2012).
Fremder, E. et al. Tumor-derived microparticles induce bone marrow-derived cell mobilization and tumor homing: a process regulated by osteopontin. Int. J. Cancer 135, 270–281 (2014).
Welford, A. F. et al. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J. Clin. Invest. 121, 1969–1973 (2011).
Hughes, R. et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75, 3479–3491 (2015).
Liu, T. et al. Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy. Oncoimmunology 7, e1436922 (2018).
Leibovich, S. J. et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-α. Nature 329, 630–632 (1987).
Sangaletti, S. et al. Oncogene-driven intrinsic inflammation induces leukocyte production of tumor necrosis factor that critically contributes to mammary carcinogenesis. Cancer Res. 70, 7764–7775 (2010).
Sprowl, J. A. et al. Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells. Breast Cancer Res. 14, R2 (2012).
Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).
Heckmann, M., Douwes, K., Peter, R. & Degitz, K. Vascular activation of adhesion molecule mRNA and cell surface expression by ionizing radiation. Exp. Cell Res. 238, 148–154 (1998).
Cox, T. R. et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–1732 (2013). This paper is one of a few published studies that demonstrates the link between LOX and ECM remodelling leading to fibrosis and metastasis. LOX-induced lung fibrosis accounts for metastatic spread.
Oh, E. T. et al. Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast. Oncogene 33, 1229–1238 (2014).
Sofia Vala, I. et al. Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis. PLOS ONE 5, e11222 (2010).
Park, H. J., Griffin, R. J., Hui, S., Levitt, S. H. & Song, C. W. Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat. Res. 177, 311–327 (2012).
Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).
Nikolinakos, P. G. et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 70, 2171–2179 (2010).
Ebos, J. M., Lee, C. R., Christensen, J. G., Mutsaers, A. J. & Kerbel, R. S. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc. Natl Acad. Sci. USA 104, 17069–17074 (2007). This paper is one of the first to demonstrate a host systemic effect in response to the anti-angiogenic receptor tyrosine kinase inhibitor sunitinib. Circulating factors whose levels change in response to treatment are suggested as biomarkers for drug activity.
Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 116, 2610–2621 (2006).
Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014).
Scholz, A. et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med. 8, 39–57 (2016).
Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat. Biotechnol. 25, 911–920 (2007).
Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).
Keklikoglou, I. et al. Periostin limits tumor response to VEGFA inhibition. Cell Rep. 22, 2530–2540 (2018).
Cooke, V. G. et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21, 66–81 (2012).
Crawford, Y. & Ferrara, N. Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies. Trends Pharmacol. Sci. 30, 624–630 (2009).
Crawford, Y. et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15, 21–34 (2009).
Guan, H., Jia, S. F., Zhou, Z., Stewart, J. & Kleinerman, E. S. Herceptin down-regulates HER-2/neu and vascular endothelial growth factor expression and enhances taxol-induced cytotoxicity of human Ewing’s sarcoma cells in vitro and in vivo. Clin. Cancer Res. 11, 2008–2017 (2005).
Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).
Minder, P., Zajac, E., Quigley, J. P. & Deryugina, E. I. EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation. Neoplasia 17, 634–649 (2015).
Wang, W. M. et al. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma. PLOS ONE 10, e0119723 (2015).
Forget, P., Simonet, O. & De Kock, M. Cancer surgery induces inflammation, immunosuppression and neo-angiogenesis, but is it influenced by analgesics? F1000Res 2, 102 (2013).
Hofer, S. O. et al. The effect of surgical wounding on tumour development. Eur J. Surg. Oncol. 25, 231–243 (1999).
Curigliano, G. et al. Systemic effects of surgery: quantitative analysis of circulating basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β) in patients with breast cancer who underwent limited or extended surgery. Breast Cancer Res. Treat 93, 35–40 (2005).
Bono, A. et al. Angiogenic cells, macroparticles and RNA transcripts in laparoscopic vs open surgery for colorectal cancer. Cancer Biol. Ther. 10, 682–685 (2010).
Langenberg, M. H. et al. Liver surgery induces an immediate mobilization of progenitor cells in liver cancer patients: a potential role for G-CSF. Cancer Biol. Ther. 9, 743–748 (2010).
Rachman-Tzemah, C. et al. Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases. Cell Rep. 19, 774–784 (2017). This paper describes a novel mechanism by which surgery induces metastasis. The paper demonstrates in mice that lungs are more prone to metastatic seeding after an abdominal surgical incision, owing to ECM remodelling at sites distant from the surgical wound.
Folkman, J. Angiogenesis and apoptosis. Semin. Cancer Biol. 13, 159–167 (2003).
Retsky, M. et al. Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients. Breast Cancer Res. 6, R372–R374 (2004).
Voloshin, T., Gingis-Velitski, S. & Shaked, Y. The angiogenic profile of colorectal cancer patients following open or laparoscopic colectomy. Cancer Biol. Ther. 10, 686–688 (2010).
Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).
Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).
Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).
Gingis-Velitski, S. et al. Host response to short-term, single-agent chemotherapy induces matrix metalloproteinase-9 expression and accelerates metastasis in mice. Cancer Res. 71, 6986–6996 (2011).
Daenen, L. G. et al. Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. Cancer Res. 71, 6976–6985 (2011). Along with reference 119, this paper is one of the first studies describing a true systemic host response phenomenon following treatment with chemotherapeutic drugs.
Kuonen, F., Secondini, C. & Ruegg, C. Molecular pathways: emerging pathways mediating growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. Clin. Cancer Res. 18, 5196–5202 (2012).
Vilalta, M., Rafat, M., Giaccia, A. J. & Graves, E. E. Recruitment of circulating breast cancer cells is stimulated by radiotherapy. Cell Rep. 8, 402–409 (2014).
Vilalta, M., Rafat, M. & Graves, E. E. Effects of radiation on metastasis and tumor cell migration. Cell Mol. Life Sci. 73, 2999–3007 (2016).
Shree, T. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011). This important paper demonstrates how macrophages contribute to tumour resistance, showing that, in response to several cytotoxic agents, macrophages express various cathepsins, which in turn protect tumour cells from the cytotoxic effect of the drug.
Voloshin, T. et al. Blocking IL1β pathway following paclitaxel chemotherapy slightly inhibits primary tumor growth but promotes spontaneous metastasis. Mol. Cancer Ther. 14, 1385–1394 (2015).
Arwert, E. N. et al. A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation. Cell Rep. 23, 1239–1248 (2018).
Nakasone, E. S. et al. Imaging tumor–stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).
Gutter-Kapon, L. et al. Heparanase is required for activation and function of macrophages. Proc. Natl Acad. Sci. USA 113, E7808–E7817 (2016).
Rastogi, P. et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J. Clin. Oncol. 26, 778–785 (2008).
Symmans, W. F. et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414–4422 (2007).
Rohan, T. E. et al. Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J. Natl Cancer Inst. 106 (2014).
Sparano, J. A. et al. A metastasis biomarker (MetaSite Breast Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer. NPJ Breast Cancer 3, 42 (2017).
Karagiannis, G. S. et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci. Transl Med. 9, eaan0026 (2017). This seminal paper provides both preclinical and clinical evidence for the host response to chemotherapy and its contribution to metastasis. Specifically, the study reports the formation of TMEM in patients with breast cancer who underwent neoadjuvant chemotherapy, which increases the potential for metastasis.
DeMichele, A., Yee, D. & Esserman, L. Mechanisms of resistance to neoadjuvant chemotherapy in breast cancer. N. Engl. J. Med. 377, 2287–2289 (2017).
Timaner, M. et al. Dequalinium blocks macrophage-induced metastasis following local radiation. Oncotarget 6, 27537–27554 (2015).
Keklikoglou, I. et al. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat. Cell Biol. 21, 190–202 (2019). This publication demonstrates that tumour cells at the primary tumour site secrete exosomes in response to chemotherapy, thereby contributing to the formation of the pre-metastatic niche and tumour cell seeding.
Chang, Y. S., Jalgaonkar, S. P., Middleton, J. D. & Hai, T. Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, E7159–E7168 (2017).
Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).
Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009). This study is one of the first to demonstrate that anti-angiogenic drugs inhibit primary tumour growth but at the same time induce metastasis in mouse tumour models. Host systemic effects in response to antiangiogenic drugs are suggested to be responsible for this phenomenon.
Kerbel, R. S. & Ebos, J. M. Peering into the aftermath: the inhospitable host? Nat. Med. 16, 1084–1085 (2010).
Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl Med. 8, 360ra135 (2016). This study demonstrates that anti-angiogenic drugs may support liver metastasis in patients with colorectal cancer. Specifically, anti-VEGF therapy promotes the secretion of ECM molecules, which in turn contribute to tumour stiffness and metastasis.
Ando, N. et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group study—JCOG9204. J. Clin. Oncol. 21, 4592–4596 (2003).
Hofman, V. et al. Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma: comparison of the efficacy of the CellSearch Assay™ and the isolation by size of epithelial tumor cell method. Int. J. Cancer 129, 1651–1660 (2011).
Retsky, M. et al. NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup. Breast Cancer Res. Treat 134, 881–888 (2012).
Takemoto, Y. et al. The mobilization and recruitment of c-kit+ cells contribute to wound healing after surgery. PLOS ONE 7, e48052 (2012).
Ceelen, W., Pattyn, P. & Mareel, M. Surgery, wound healing, and metastasis: recent insights and clinical implications. Crit. Rev. Oncol. Hematol. 89, 16–26 (2014).
Krall, J. A. et al. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci. Transl Med. 10, eaan3464 (2018). This mechanistic study describes how surgery-induced immune modulation contributes to the outgrowth of dormant tumours at metastatic sites.
Panigrahy, D. et al. Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases. J. Clin. Invest. 129, 2964–2979 (2019).
van der Bij, G. J. et al. The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann. Surg. 249, 727–734 (2009).
Jemal, A. et al. Cancer statistics, 2003. CA Cancer J. Clin. 53, 5–26 (2003).
Demicheli, R., Abbattista, A., Miceli, R., Valagussa, P. & Bonadonna, G. Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res. Treat 41, 177–185 (1996).
Shibue, T. & Weinberg, R. A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017).
Roodhart, J. M. et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20, 370–383 (2011).
Timaner, M. et al. Therapy-educated mesenchymal stem cells enrich for tumor-initiating cells. Cancer Res. 78, 1253–1265 (2018).
Chan, T. S. et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J. Exp. Med. 213, 2967–2988 (2016). This paper provides an explanation for tumour resistance following MTD chemotherapy in desmoplastic tumours.
Su, S. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856.e16 (2018). This study demonstrates that only a subset of CAFs promote the enrichment of CSCs in response to chemotherapy.
Olson, O. C., Kim, H., Quail, D. F., Foley, E. A. & Joyce, J. A. Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep. 19, 101–113 (2017).
Beyar-Katz, O. et al. Pro-inflammatory macrophages promote multiple myeloma resistance to bortezomib therapy. Mol. Cancer Res. https://doi.org/10.1158/1541-7786.MCR-19-0487 (2019).
Ma, J., Song, X., Xu, X. & Mou, Y. Cancer-associated fibroblasts promote the chemo-resistance in gastric cancer through secreting IL-11 targeting JAK/STAT3/Bcl2 pathway. Cancer Res. Treat 51, 194–210 (2019).
Kim, S. J. et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13, 286–298 (2011).
Lehuédé, C. et al. Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP). Breast Cancer Res. 21, 7 (2019).
Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 18, 1359–1368 (2012).
Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011).
Ahmed, K. M., Zhang, H. & Park, C. C. NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells. Cancer Res. 73, 3737–3748 (2013).
Hanahan, D., Bergers, G. & Bergsland, E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J. Clin. Invest. 105, 1045–1047 (2000).
Pasquier, E., Kavallaris, M. & Andre, N. Metronomic chemotherapy: new rationale for new directions. Nat. Rev. Clin. Oncol. 7, 455–465 (2010).
Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).
Shaked, Y. et al. Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy. Cancer Res. 76, 5983–5993 (2016).
Pietras, K. & Hanahan, D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J. Clin. Oncol. 23, 939–952 (2005).
Shaked, Y. et al. Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res. 65, 7045–7051 (2005).
Simkens, L. H. et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385, 1843–1852 (2015).
Takahashi, Y., Mai, M., Sawabu, N. & Nishioka, K. A pilot study of individualized maximum repeatable dose (iMRD), a new dose finding system, of weekly gemcitabine for patients with metastatic pancreas cancer. Pancreas 30, 206–210 (2005).
Benguigui, M. et al. Dose- and time-dependence of the host-mediated response to paclitaxel therapy: a mathematical modeling approach. Oncotarget 9, 2574–2590 (2018).
West, J. & Newton, P. K. Chemotherapeutic dose scheduling based on tumor growth rates provides a case for low-dose metronomic high-entropy therapies. Cancer Res. 77, 6717–6728 (2017).
Chen, C. S., Doloff, J. C. & Waxman, D. J. Intermittent metronomic drug schedule is essential for activating antitumor innate immunity and tumor xenograft regression. Neoplasia 16, 84–96 (2014).
Singh, M. et al. Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J. Pathol. 227, 417–430 (2012).
Rodenhuis, S. The status of high-dose chemotherapy in breast cancer. Oncologist 5, 369–375 (2000).
Shaked, Y. & Kerbel, R. S. Antiangiogenic strategies on defense: blocking rebound by the tumor vasculature after chemotherapy. Cancer Res. 67, 7055–7058 (2007).
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
Kerbel, R. S. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312, 1171–1175 (2006).
Scagliotti, G. et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 1835–1842 (2010).
Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).
Lyons, Y. A. et al. Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy. Oncotarget 8, 96496–96505 (2017).
Salvagno, C. et al. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response. Nat. Cell Biol. 21, 511–521 (2019).
Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015). This review focuses on the role of macrophages in promoting therapy resistance mainly by modulating the immune system, and also discusses the therapeutic potential of blocking macrophage recruitment to the treated tumour site.
Harney, A. S. et al. The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol. Cancer Ther. 16, 2486–2501 (2017).
Voloshin, T. et al. G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist. Blood 118, 3426–3435 (2011).
Kim, J. et al. Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J. Clin. Oncol. 23, 2744–2753 (2005).
Bracci, L., Schiavoni, G., Sistigu, A. & Belardelli, F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 21, 15–25 (2014).
Gartung, A. et al. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proc. Natl Acad. Sci. USA 116, 1698–1703 (2019).
Sulciner, M. L. et al. Resolvins suppress tumor growth and enhance cancer therapy. J. Exp. Med. 215, 115–140 (2018).
Pueyo, G. et al. Cetuximab may inhibit tumor growth and angiogenesis induced by ionizing radiation: a preclinical rationale for maintenance treatment after radiotherapy. Oncologist 15, 976–986 (2010).
Fuentes-Antras, J., Provencio, M. & Diaz-Rubio, E. Hyperprogression as a distinct outcome after immunotherapy. Cancer Treat Rev. 70, 16–21 (2018).
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). This study is one of the first that provides a mechanism explaining hyperprogression during treatment with ICIs. The authors demonstrate that hyperprogressive gastric carcinomas from patients treated with anti-PD1 therapy are infiltrated with proliferating T reg cells that suppress immune activity.
Lo Russo, G. et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin. Cancer Res. 25, 989–999 (2019).
Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).
Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).
Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).
Pastula, A. & Marcinkiewicz, J. Myeloid-derived suppressor cells: a double-edged sword? Int. J. Exp. Pathol. 92, 73–78 (2011).
Ma, Y. et al. Tumor necrosis factor is dispensable for the success of immunogenic anticancer chemotherapy. Oncoimmunology 2, e24786 (2013).
Aymeric, L. et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res. 70, 855–858 (2010).
Ciampricotti, M., Hau, C. S., Doornebal, C. W., Jonkers, J. & de Visser, K. E. Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nat. Med. 18, 344–346 (2012).
Baumeister, S. H., Freeman, G. J., Dranoff, G. & Sharpe, A. H. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol. 34, 539–573 (2016).
Azami, A. et al. Abscopal effect following radiation monotherapy in breast cancer: a case report. Mol. Clin. Oncol. 9, 283–286 (2018).
Yan, Y. et al. Combining immune checkpoint inhibitors with conventional cancer therapy. Front. Immunol. 9, 1739 (2018).
Derer, A., Frey, B., Fietkau, R. & Gaipl, U. S. Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol. Immunother. 65, 779–786 (2016).
Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
Kasmann, L. et al. State of clinical research of radiotherapy/chemoradiotherapy and immune checkpoint inhibitor therapy combinations in solid tumours—a German radiation oncology survey. Eur. J. Cancer 108, 50–54 (2019).
Wang, X. et al. Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1–IGF1R signalling in epithelial ovarian cancer. Br. J. Cancer 117, 1371–1382 (2017).
Oyama, T. et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-κB activation in hemopoietic progenitor cells. J. Immunol. 160, 1224–1232 (1998).
Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878–4886 (2003).
Osada, T. et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol. Immunother. 57, 1115–1124 (2008).
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).
Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).
Valpione, S. et al. Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade. J. Transl Med. 16, 94 (2018).
Tsukamoto, H. et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 78, 5011–5022 (2018).
Li, J. et al. Targeting interleukin-6 (IL-6) sensitizes anti-PD-L1 treatment in a colorectal cancer preclinical model. Med. Sci. Monit. 24, 5501–5508 (2018).
Ilieva, K. M. et al. Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma. Mol. Cancer Ther. 13, 2769–2783 (2014).
Sasada, T., Azuma, K., Ohtake, J. & Fujimoto, Y. Immune responses to epidermal growth factor receptor (EGFR) and their application for cancer treatment. Front. Pharmacol. 7, 405 (2016).
Concha-Benavente, F. & Ferris, R. L. Reversing EGFR mediated immunoescape by targeted monoclonal antibody therapy. Front. Pharmacol. 8, 332 (2017).
Luke, J. J. Comprehensive clinical trial data summation for BRAF–MEK inhibition and checkpoint immunotherapy in metastatic melanoma. Oncologist https://doi.org/10.1634/theoncologist.2018-0876 (2019).
Krieg, C. et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat. Med. 24, 144–153 (2018).
Sathyanarayanan, V. & Neelapu, S. S. Cancer immunotherapy: strategies for personalization and combinatorial approaches. Mol. Oncol. 9, 2043–2053 (2015).
Cassetta, L. & Kitamura, T. Macrophage targeting: opening new possibilities for cancer immunotherapy. Immunology 155, 285–293 (2018).
Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057–5069 (2014).
Al-Lazikani, B., Banerji, U. & Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30, 679–692 (2012).
Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).
Harris, S. J., Brown, J., Lopez, J. & Yap, T. A. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol. Med. 13, 171–193 (2016).
Bertolini, F., Sukhatme, V. P. & Bouche, G. Drug repurposing in oncology—patient and health systems opportunities. Nat. Rev. Clin. Oncol. 12, 732–742 (2015).
Reinhold, W. C. et al. Using drug response data to identify molecular effectors, and molecular “omic” data to identify candidate drugs in cancer. Hum Genet. 134, 3–11 (2015).
Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502.e15 (2017).
Gopalakrishnan, V., Helmink, B. A., Spencer, C. N., Reuben, A. & Wargo, J. A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33, 570–580 (2018).
McQuade, J. L., Daniel, C. R., Helmink, B. A. & Wargo, J. A. Modulating the microbiome to improve therapeutic response in cancer. Lancet. Oncol. 20, e77–e91 (2019).
Day, D. & Siu, L. L. Approaches to modernize the combination drug development paradigm. Genome Med. 8, 115 (2016).
[No authors listed] Rationalizing combination therapies. Nat. Med. 23, 1113 (2017).
Pastoriza, J. M. et al. Black race and distant recurrence after neoadjuvant or adjuvant chemotherapy in breast cancer. Clin. Exp. Metastasis 35, 613–623 (2018).
Martin, D. N. et al. Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLOS ONE 4, e4531 (2009).
Koru-Sengul, T. et al. Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians. Breast Cancer Res. Treat 158, 113–126 (2016).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).
Liu, W. M., Fowler, D. W., Smith, P. & Dalgleish, A. G. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br. J. Cancer 102, 115–123 (2010).
Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. & Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005).
Reynders, K., Illidge, T., Siva, S., Chang, J. Y. & De Ruysscher, D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 41, 503–510 (2015). This review focuses on the combination of immunotherapy and radiotherapy. The review raises the hypothesis that the abscopal effect occurring in a subset of patients who undergo radiotherapy can be enhanced with ICIs.
The author thanks the referees of this manuscript who provided excellent comments that substantially improved the Review. The author also thanks R. Kerbel, J. Condeelis and M. Oktay for their comments and suggestions throughout the writing process. It is with regret that not all relevant studies could be cited due to space limitation. This Review and many of the original studies published by the author on this specific subject have been supported by European Research Council (ERC) grants (current 771112).
The author is a co-founder of OncoHost, a biotechnology company that utilizes the host response profile in the clinical setting in order to improve anticancer therapies. The author is listed on several patents related to host responses to anticancer drugs.
Peer review information
Nature Reviews Cancer thanks M. De Palma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Tumour-associated macrophages
(TAMs). A heterogeneous population of differentiated monocytes found in the microenvironment of solid tumours, mainly consisting of cells with immunosuppressive functions (also known as M2-like macrophages) as well as a minor population of cells with pro-inflammatory functions (also known as M1-like macrophages).
- ATP-binding cassette (ABC) transporters
Transporter proteins composed of transmembrane and ATPase protein subunits that take up or export various substrates across the cell membrane. In cancer cells, they contribute to therapy resistance via their ability to expel drugs from the cell.
- Tubulin-binding agents
A family of anti-neoplastic chemotherapeutic drugs that interfere with the depolarization or polymerization of microtubules required for cell mitosis. As the rapidly proliferating malignant cells cannot divide in the presence of tubulin-binding agents, they eventually undergo apoptosis.
- Alkylating agents
A family of anti-neoplastic chemotherapeutic drugs that act to replace hydrogen with an alkyl group in the replicated DNA during cell proliferation. The alkyl group is attached to the guanine base of the DNA, thus causing DNA damage and, ultimately, cell apoptosis.
- Anti-metabolite agents
A family of anti-neoplastic chemotherapeutic drugs that interfere with the metabolic pathway of DNA replication in S phase, ultimately inducing cell apoptosis. Among these agents are folic acid antagonists, and purine and pyrimidine anti-metabolites.
- Myeloid cells
Leukocytes from the haematopoietic myeloid lineage. These are usually premature cells that differentiate into monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes and megakaryocytes.
- Extracellular vesicles
(EVs). Lipid bilayer particles that contain DNA, RNA and proteins and that are released from the cell surface membrane. They vary in size (usually between 50 and 500 µm) and are categorized as exosomes, microparticles and apoptotic bodies.
- Thymus-associated endothelial cells
Endothelial cells residing in the thymus that contribute to the regeneration of thymus tissue following radiation.
- Bronchoalveolar lavage
An invasive medical procedure involving the instillation of saline solution into a subsegment of the lung area. The liquid is then retrieved by suction and analysed for cells, protein content and foreign materials.
A ligand of the epidermal growth factor receptor (EGFR) expressed by epithelial cells. Its signalling through EGFR contributes to the development and growth of normal epithelial cells. In cancer, it promotes tumour cell proliferation.
A ligand of the epidermal growth factor receptor that contributes to inflammation, wound healing and tissue repair.
The formation of new lymphatic vessels from pre-existing lymphatic vessels, in a process similar to angiogenesis. In cancer, lymphangiogenesis is associated with metastasis.
- Vascular-disrupting agents
(VDAs). A family of drugs with potent tumour vessel disruption ability. These cytotoxic-like agents (usually tubulin-binding or tubulin-destabilizing agents) rapidly promote cancer vessel collapse leading to necrosis.
Bone marrow-derived pro-angiogenic haematopoietic cells that were shown to contribute to tumour angiogenesis. They are usually localized in the perivascular zone of the growing blood vessel and contribute to its integrity.
The process of systemic formation of blood vessels. As opposed to angiogenesis, which is a local process of blood vessel formation from pre-existing vessels, vasculogenesis is mediated by systemic mobilization of bone marrow-derived pro-angiogenic cells, such as endothelial precursor cells, which incorporate to generate blood vessels.
The formation or thickening of connective tissue in response to injury or chronic inflammation.
A procedure in which a fibre-optic device is usually inserted into the abdomen in order to fulfil a surgical procedure. It is sometimes used instead of open surgery to minimize recovery time.
- Tumour microenvironment of metastasis
(TMEM). An anatomical structure within solid tumours composed of a cancer cell and a perivascularly located macrophage expressing TIE2 and vascular endothelial growth factor (VEGF). When both of these cells tightly bind to a blood vessel endothelial cell, the secretion of local VEGF contributes to blood vessel permeability, opening a doorway through which tumour cells can extravasate and disseminate from the primary tumour site.
- Pre-metastatic niche
A physical area in a secondary non-malignant site that provides a favourable environment for circulating tumour cells to seed and proliferate in order to establish a metastatic lesion.
Polyunsaturated fatty acid metabolites that, in response to injury and subsequent inflammation, resolve inflammation and help restore tissue homeostasis.
- Desmoplastic tumours
Tumours containing a large amount of dense connective and fibrous tissue, such as pancreatic ductal adenocarcinoma.
A relatively rare haematological malignancy, classed as a subtype of acute myeloid leukaemia arising from malignant erythroid blasts. Owing to the lack of differentiated erythroid cells, the disease is characterized by anaemia, thrombocytopenia and leukopenia.
- Epoxide hydrolase
A class of enzymes that metabolize epoxide residues into hydroxyls. There are several enzymes in this family, distinguished from each other by their preferred substrates. They are known to detoxify genotoxic compounds and play a role in physiological signalling.
- Abscopal effect
A rare phenomenon in which local radiation causes tumour shrinkage not only at the irradiated tumour site but also at distant tumour sites (usually metastatic lesions) located outside the field of irradiation.
About this article
Cite this article
Shaked, Y. The pro-tumorigenic host response to cancer therapies. Nat Rev Cancer 19, 667–685 (2019). https://doi.org/10.1038/s41568-019-0209-6
Journal for ImmunoTherapy of Cancer (2021)
Pharmacodynamic biomarkers in metronomic chemotherapy: multiplex cytokine measurements in gastrointestinal cancer patients
Clinical and Experimental Medicine (2021)
International Journal of Molecular Sciences (2021)
Pharmacology & Therapeutics (2021)
Tumor-permeated bioinspired theranostic nanovehicle remodels tumor immunosuppression for cancer therapy