Chimeric antigen receptor (CAR)-T cell therapy has achieved successful outcomes against hematological malignancies and provided a new impetus for treating solid tumors. However, the efficacy of CAR-T cells for solid tumors remains unsatisfactory. The tumor microenvironment has an important role in interfering with and inhibiting the effector function of immune cells, among which upregulated inhibitory checkpoint receptors, soluble suppressive cytokines, altered chemokine expression profiles, aberrant vasculature, complicated stromal composition, hypoxia and abnormal tumor metabolism are major immunosuppressive mechanisms. In this review, we summarize the inhibitory factors that affect the function of CAR-T cells in tumor microenvironment and discuss approaches to improve CAR-T cell efficacy for solid tumor treatment by targeting those barriers.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 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.
Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra138 (2013).
Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).
Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).
Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).
Prasad, V. Immunotherapy: Tisagenlecleucel - the first approved CAR-T-cell therapy: implications for payers and policy makers. Nat. Rev. Clin. Oncol. 15, 11–12 (2018).
Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
Schaft, N. The landscape of CAR-T cell clinical trials against solid tumors-a comprehensive overview. Cancers 12, 2567 (2020).
Xianbao Zhan, B. W. et al. Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. J. Clin. Oncol. 37, 1 (2019).
Beatty, G. L. et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018).
Moon, E. K. et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17, 4719–4730 (2011).
Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).
Shi, D. et al. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase I trials. Clin. Cancer Res. 26, 3979–3989 (2020).
Hegde, M. et al. Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma. J. Clin. Oncol. 35, 10508 (2017).
Ahmed, N. et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma A phase 1 dose-escalation trial. JAMA Oncol. 3, 1094–1101 (2017).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-Positive sarcoma. J. Clin. Oncol. 33, 1688 (2015) .
Heczey, A. et al. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol. Ther. 25, 2214–2224 (2017).
O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).
Thistlethwaite, F. C. et al. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol. Immunother. 66, 1425–1436 (2017).
Thistlethwaite, F. C. et al. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol. Immunother. 66, 1425–1436 (2017).
Zhang, C. et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol. Ther. 25, 1248–1258 (2017).
Katz, S. C. et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA(+) liver metastases. Clin. Cancer Res. 21, 3149–3159 (2015).
Junghans, R. P. et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate 76, 1257–1270 (2016).
Fousek, K. & Ahmed, N. The evolution of T-cell therapies for solid malignancies. Clin. Cancer Res. 21, 3384–3392 (2015).
Slaney, C. Y., Kershaw, M. H. & Darcy, P. K. Trafficking of T cells into tumors. Cancer Res. 74, 7168–7174 (2014).
Korman, A. J., Peggs, K. S. & Allison, J. P. Checkpoint blockade in cancer immunotherapy. Adv. Immunol. 90, 297–339 (2006).
Ugel, S. et al. Therapeutic targeting of myeloid-derived suppressor cells. Curr. Opin. Pharm. 9, 470–481 (2009).
Tanaka, A. & Sakaguchi, S. Targeting Treg cells in cancer immunotherapy. Eur. J. Immunol. 49, 1140–1146 (2019).
Beckermann, K. E., Dudzinski, S. O. & Rathmell, J. C. Dysfunctional T cell metabolism in the tumor microenvironment. Cytokine Growth Factor Rev. 35, 7–14 (2017).
Counihan, J. L., Grossman, E. A. & Nomura, D. K. Cancer metabolism: current understanding and therapies. Chem. Rev. 118, 6893–6923 (2018).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell Biol. 25, 9543–9553 (2005).
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).
Park, J. J. et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 116, 1291–1298 (2010).
Blank, C. U. & Enk, A. Therapeutic use of anti-CTLA-4 antibodies. Int. Immunol. 27, 3–10 (2015).
John, L. B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013).
Moon, E. K. et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin. Cancer Res. 20, 4262–4273 (2014).
Gargett, T. et al. GD2-specific CAR T cells undergo potent activation and deletion following antigen encounter but can be protected from activation-induced cell death by PD-1 blockade. Mol. Ther. 24, 1135–1149 (2016).
Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest 126, 3130–3144 (2016).
Burga, R. A. et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol. Immunother. 64, 817–829 (2015).
Tanoue, K. et al. Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors. Cancer Res. 77, 2040–2051 (2017).
Chong, E. A. et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129, 1039–1041 (2017).
Suarez, E. R. et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7, 34341–34355 (2016).
Li, S. et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin. Cancer Res. 23, 6982–6992 (2017).
Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).
Liu, X. et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016).
Dozier, J., Chen, N., Saini, J., Chintala, N. & Adusumilli, P. MA11.01 comparative efficacy of T-cell intrinsic versus extrinsic PD-1 blockade to overcome PD-L1+ tumor-mediated exhaustion. J. Thorac. Oncol. 13, S392 (2018).
Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737 (2017).
Hu, W. et al. CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. Cancer Immunol. Immunother. 68, 365–377 (2019).
Gautron, A. S. et al. Fine and predictable tuning of TALEN gene editing targeting for improved T cell adoptive immunotherapy. Mol. Ther. Nucleic Acids 9, 312–321 (2017).
Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).
Ren, J. & Zhao, Y. Advancing chimeric antigen receptor T cell therapy with CRISPR/Cas9. Protein Cell 8, 634–643 (2017).
Grosser, R., Cherkassky, L., Chintala, N. & Adusumilli, P. S. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36, 471–482 (2019).
Schildberg, F. A., Klein, S. R., Freeman, G. J. & Sharpe, A. H. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44, 955–972 (2016).
Lee, Y. H. et al. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res. 27, 1034–1045 (2017).
Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Yanagie, H., Hisa, T., Ono, M. & Eriguchi, M. Chemokine and chemokine receptor related to cancer metastasis. Gan Kagaku Ryoho 37, 2052–2057 (2010).
Lee, H. J., Song, I. C., Yun, H. J., Jo, D. Y. & Kim, S. CXC chemokines and chemokine receptors in gastric cancer: from basic findings towards therapeutic targeting. World J. Gastroenterol. 20, 1681–1693 (2014).
Dimberg, A. Chemokines in angiogenesis. Curr. Top. Microbiol. Immunol. 341, 59–80 (2010).
Keeley, E. C., Mehrad, B. & Strieter, R. M. Chemokines as mediators of tumor angiogenesis and neovascularization. Exp. Cell Res. 317, 685–690 (2011).
Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).
Pivarcsi, A. et al. Tumor immune escape by the loss of homeostatic chemokine expression. Proc. Natl Acad. Sci. USA 104, 19055–19060 (2007).
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475, 226–230 (2011).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Nagarsheth, N. et al. PRC2 epigenetically silences Th1-Type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res. 76, 275–282 (2016).
Wang, L. et al. Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol. Res. 3, 1030–1041 (2015).
Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339–1346 (2001).
Kryczek, I. et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 65, 465–472 (2005).
Bertolini, F. et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin’s lymphoma. Cancer Res. 62, 3106–3112 (2002).
Rubin, J. B. et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc. Natl Acad. Sci. USA 100, 13513–13518 (2003).
Liang, Z. et al. Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 65, 967–971 (2005).
O’Hara, M. H. et al. Safety and pharmacokinetics of CXCR4 peptide antagonist, LY2510924, in combination with durvalumab in advanced refractory solid tumors. J. Pancreat. Cancer 6, 21–31 (2020).
Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).
Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).
Long, H. et al. Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-kappaB-mediated MMP-9 upregulation. Stem Cells 30, 2309–2319 (2012).
Nywening, T. M. et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut 67, 1112–1123 (2018).
Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016).
Kershaw, M. H. et al. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum. Gene Ther. 13, 1971–1980 (2002).
Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009).
Craddock, J. A. et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780–788 (2010).
Jin, L. et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat. Commun. 10, 4016 (2019).
Liu, G. et al. CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma. Eur. J. Immunol. 50, 712–724 (2020).
Adachi, K. et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat. Biotechnol. 36, 346–351 (2018).
Chung, A. S., Lee, J. & Ferrara, N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat. Rev. Cancer 10, 505–514 (2010).
Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).
Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).
Jin, Y. et al. RGS5, a hypoxia-inducible apoptotic stimulator in endothelial cells. J. Biol. Chem. 284, 23436–23443 (2009).
Wang, J. et al. Hepatic regulator of G protein signaling 5 ameliorates Nonalcoholic Fatty Liver Disease by suppressing Transforming Growth Factor Beta-Activated Kinase 1-c-Jun-N-Terminal Kinase/p38 Signaling. Hepatology 73, 104–125 (2021).
Li, B. et al. Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin. Cancer Res. 12, 6808–6816 (2006).
Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).
Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).
Chinnasamy, D. et al. Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J. Clin. Invest. 120, 3953–3968 (2010).
Wang, W. et al. Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency. Gene Ther. 20, 970–978 (2013).
Niederman, T. M. et al. Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors. Proc. Natl Acad. Sci. USA 99, 7009–7014 (2002).
Santoro, S. P. et al. T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression. Cancer Immunol. Res. 3, 68–84 (2015).
Fu, X., Rivera, A., Tao, L. & Zhang, X. Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery. Int. J. Cancer 133, 2483–2492 (2013).
Byrd, T. T. et al. TEM8/ANTXR1-specific CAR T cells as a targeted therapy for triple-negative breast cancer. Cancer Res. 78, 489–500 (2018).
Xie, Y. J. et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc. Natl Acad. Sci. USA 116, 7624–7631 (2019).
Zhuang, X. et al. CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth. JCI Insight 5, e138808 (2020).
Petrovic, K. et al. TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo. PLoS ONE 14, e0224015 (2019).
Curnis, F. et al. Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Res. 62, 867–874 (2002).
Pasqualini, R. et al. Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res. 60, 722–727 (2000).
van Laarhoven, H. W. et al. Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas. Invest. N. Drugs 24, 27–36 (2006).
Calcinotto, A. et al. Targeting TNF-alpha to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J. Immunol. 188, 2687–2694 (2012).
Bellone, M., Calcinotto, A. & Corti, A. Won’t you come on in? How to favor lymphocyte infiltration in tumors. Oncoimmunology 1, 986–988 (2012).
Dondossola, E. et al. Chromogranin A restricts drug penetration and limits the ability of NGR-TNF to enhance chemotherapeutic efficacy. Cancer Res. 71, 5881–5890 (2011).
Johansson, A., Hamzah, J., Payne, C. J. & Ganss, R. Tumor-targeted TNFalpha stabilizes tumor vessels and enhances active immunotherapy. Proc. Natl Acad. Sci. USA 109, 7841–7846 (2012).
Curnis, F. et al. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat. Biotechnol. 18, 1185–1190 (2000).
Lorusso, D. et al. Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients. Br. J. Cancer 107, 37–42 (2012).
Werb, Z. & Lu, P. The role of stroma in tumor development. Cancer J. 21, 250–253 (2015).
Scanlan, M. J. et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc. Natl Acad. Sci. USA 91, 5657–5661 (1994).
Garin-Chesa, P., Old, L. J. & Rettig, W. J. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc. Natl Acad. Sci. USA 87, 7235–7239 (1990).
Busek, P., Mateu, R., Zubal, M., Kotackova, L. & Sedo, A. Targeting fibroblast activation protein in cancer—prospects and caveats. Front. Biosci. 23, 1933–1968 (2018).
Tran, E. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 210, 1125–1135 (2013).
Roberts, E. W. et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 210, 1137–1151 (2013).
Kakarla, S. et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol. Ther. 21, 1611–1620 (2013).
Schuberth, P. C. et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J. Transl. Med. 11, 187 (2013).
Wang, L. C. et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014).
Lo, A. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Friberg, M. et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J. Cancer 101, 151–155 (2002).
Frumento, G. et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196, 459–468 (2002).
Ninomiya, S. et al. Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann. Hematol. 90, 409–416 (2011).
Ninomiya, S. et al. Indoleamine 2,3-dioxygenase expression and serum kynurenine concentrations in patients with diffuse large B-cell lymphoma. Leuk. Lymphoma 53, 1143–1145 (2012).
Liu, X. et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115, 3520–3530 (2010).
Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013).
Wainwright, D. A. et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin. Cancer Res. 20, 5290–5301 (2014).
Spranger, S. et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J. Immunother. Cancer 2, 3 (2014).
Ninomiya, S. et al. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125, 3905–3916 (2015).
Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).
Barsoum, I. B., Smallwood, C. A., Siemens, D. R. & Graham, C. H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74, 665–674 (2014).
Messai, Y. et al. Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible factor-2 alpha, is regulated by von hippel-lindau gene mutation status. Eur. Urol. 70, 623–632 (2016).
Deng, J. et al. Hypoxia-induced VISTA promotes the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Immunol. Res. 7, 1079–1090 (2019).
Soto-Pantoja, D. R. et al. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res. 74, 6771–6783 (2014).
Zhang, H. et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc. Natl Acad. Sci. USA 112, E6215–E6223 (2015).
Hasmim, M. et al. Hypoxia-dependent inhibition of tumor cell susceptibility to CTL-mediated lysis involves NANOG induction in target cells. J. Immunol. 187, 4031–4039 (2011).
Baginska, J. et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl Acad. Sci. USA 110, 17450–17455 (2013).
Yan, W. H. HLA-G expression in cancers: potential role in diagnosis, prognosis and therapy. Endocr. Metab. Immune Disord. Drug Targets 11, 76–89 (2011).
Kren, L. et al. Expression of immune-modulatory molecules HLA-G and HLA-E by tumor cells in glioblastomas: an unexpected prognostic significance? Neuropathology 31, 129–134 (2011).
Andersson, E. et al. Non-classical HLA-class I expression in serous ovarian carcinoma: Correlation with the HLA-genotype, tumor infiltrating immune cells and prognosis. Oncoimmunology 5, e1052213 (2016).
Xie, H. & Simon, M. C. Oxygen availability and metabolic reprogramming in cancer. J. Biol. Chem. 292, 16825–16832 (2017).
Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11, 393–410 (2011).
Wigerup, C., Pahlman, S. & Bexell, D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharm. Ther. 164, 152–169 (2016).
Dannenberg, A. J. & Subbaramaiah, K. Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 4, 431–436 (2003).
Sitkovsky, M. V. et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 22, 657–682 (2004).
Newick, K. et al. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol. Res. 4, 541–551 (2016).
Ligtenberg, M. A. et al. Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. J. Immunol. 196, 759–766 (2016).
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).
Jandus, C., Bioley, G., Speiser, D. E. & Romero, P. Selective accumulation of differentiated FOXP3(+) CD4 (+) T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol. Immunother. 57, 1795–1805 (2008).
Almand, B. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).
Nefedova, Y. et al. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 67, 11021–11028 (2007).
Kusmartsev, S. et al. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 63, 4441–4449 (2003).
Mirza, N. et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 66, 9299–9307 (2006).
Ni, X., Hu, G. & Cai, X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit. Rev. Food Sci. Nutr. 59, S71–S80 (2019).
Serafini, P. et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203, 2691–2702 (2006).
Tobin, R. P., Davis, D., Jordan, K. R. & McCarter, M. D. The clinical evidence for targeting human myeloid-derived suppressor cells in cancer patients. J. Leukoc. Biol. 102, 381–391 (2017).
Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).
Zheng, Y. et al. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol. Immunol. 54, 74–83 (2013).
Vila-Leahey, A. et al. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice. Oncoimmunology 5, e1151591 (2016).
Hanson, E. M., Clements, V. K., Sinha, P., Ilkovitch, D. & Ostrand-Rosenberg, S. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J. Immunol. 183, 937–944 (2009).
Molon, B. et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208, 1949–1962 (2011).
Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).
Bulliard, Y. et al. Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013).
Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).
Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).
Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).
Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl Acad. Sci. USA 110, 17945–17950 (2013).
Bulliard, Y. et al. OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy. Immunol. Cell Biol. 92, 475–480 (2014).
Arce Vargas, F. et al. Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46, 577–586 (2017).
Litzinger, M. T. et al. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 110, 3192–3201 (2007).
Foster, A. E. et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. J. Immunother. 31, 500–505 (2008).
Lacuesta, K. et al. Assessing the safety of cytotoxic T lymphocytes transduced with a dominant negative transforming growth factor-beta receptor. J. Immunother. 29, 250–260 (2006).
Zhang, L. et al. Inhibition of TGF-beta signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther. 20, 575–580 (2013).
Kloss, C. C. et al. Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol. Ther. 26, 1855–1866 (2018).
Wang, L. et al. Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor beta-insensitive CD8+ T cells. Clin. Cancer Res. 16, 164–173 (2010).
Quatromoni, J. G. et al. T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFbeta) signaling mediate superior tumor regression in an animal model of adoptive cell therapy. J. Transl. Med. 10, 127 (2012).
Prokopchuk, O., Liu, Y., Henne-Bruns, D. & Kornmann, M. Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions. Br. J. Cancer 92, 921–928 (2005).
Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).
Todaro, M. et al. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ. 15, 762–772 (2008).
Gocheva, V. et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 24, 241–255 (2010).
Roca, H. et al. IL-4 induces proliferation in prostate cancer PC3 cells under nutrient-depletion stress through the activation of the JNK-pathway and survivin up-regulation. J. Cell Biochem. 113, 1569–1580 (2012).
Leen, A. M. et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol. Ther. 22, 1211–1220 (2014).
Mohammed, S. et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol. Ther. 25, 249–258 (2017).
This work was supported by a grant from the National Natural Science Foundation of China (31821003 to X.L.) and Tsinghua-Peking Center for Life Sciences.
The authors declare no competing interests.
About this article
Cite this article
Liu, G., Rui, W., Zhao, X. et al. Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment. Cell Mol Immunol 18, 1085–1095 (2021). https://doi.org/10.1038/s41423-021-00655-2
Nature Reviews Urology (2021)
Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy
Cellular & Molecular Immunology (2021)