Tumor Cells Can Evade and Suppress Immune Activity
The complex network of activating and inhibitory pathways enables the antitumor immune response to detect and eliminate tumor cells at any point in tumor development.1 Tumor cells, however, can evolve at any phase of growth to outsmart the antitumor immune response at each stage.1,2 Tumors seek to evade or suppress the body’s natural ability to fight cancer.
The tumor microenvironment consists of different cell types that can help tumor cells evade antitumor immune activity. These cell types include immune cells, such as effector and non-effector cells, as well as structural cells surrounding the tumor known as stromal cells.3,4 Non-effector cells can suppress the antitumor immune response by inhibiting effector-cell function.3 Stromal cells can temper effector-cell antitumor activity and act as a barrier that prevents immune-cell infiltration of the tumor.3,5 As tumors evolve, they can influence the activation and composition of cells within the tumor microenvironment.2,6
Different types of tumors employ varied strategies for immune evasion; the success of these strategies determines the ability of immune cells to react to the tumor.7 Depending upon their degree of immune cell infiltration, tumors are defined on a range from noninflamed to inflamed.7
Noninflamed tumors are characterized by the poor presence of immune cells in the tumor microenvironment, most notably cytotoxic T cells.7,8 Noninflamed tumors can have an impaired ability to present tumor antigens to T cells and to direct tumor-specific T cells to the tumor.7,9 These tumors may lack expression of key secreted factors, known as chemokines, that recruit immune cells to the tumors and are less able to promote tumor-specific T-cell infiltration.8 Together, these factors limit cytotoxic T-cell activation and migration to the tumor, ultimately preventing tumor cell elimination. With few immune cells present and no need to escape elimination, tumor cell expression of inhibitory proteins is low.10,11
Inflamed tumors are marked by the presence of immune cells and can be an indicator of a pre-existing immune response.7,8,12-14 A growing body of evidence suggests the existence of a T–cell-inflamed tumor microenvironment in a major subset of advanced solid tumors.12 These cancers have a high TMB and produce a high number of tumor antigens, which can facilitate the recruitment of diverse cytotoxic T cells.7,15 Unlike noninflamed tumors, antigen presentation, as well as T-cell activation, are active processes in inflamed tumors.16 The expression of chemokines allows for infiltration of activated cytotoxic T cells to the tumor site.8,17,18 To escape detection and destruction by these immune effector cells, tumor cells may increase their expression of inhibitory proteins.11,19 One mechanism for achieving this is to upregulate factors such as the bromodomain and extraterminal domain (BET) family of proteins that regulate the expression of inhibitory proteins.20-22 These inhibitory mechanisms can prevent cytotoxic T cells from eliminating tumor cells—allowing tumor cells and immune cells to coexist within the tumor microenvironment.11,16
Can tumors be made more susceptible to immune attack?
Reestablishing the fundamental stages
that are impaired within noninflamed
tumors—presentation, infiltration, and
elimination—is a key strategy in improving the broad potential of Immuno-Oncology. Ongoing research aims to promote inflammation within tumors to increase susceptibility to antitumor immunity.
Tumor antigens, which can be sparse in noninflamed tumors, are required for the initiation of an adaptive antitumor immune response.7,23 In addition to mutated proteins specific to tumor cells, proteins that are highly expressed on tumor cells, may also serve as tumor antigens with the potential to activate cytotoxic T cells.24-26 Preclinical data may suggest that promoting tumor cell death—by cytotoxic agents such as chemotherapeutics, irradiation, or infection with oncolytic viruses—can stimulate the release of tumor antigens and can initiate an immune response.27-33 Other preclinical data suggest that vaccines may introduce tumor antigens to APCs and stimulate cytotoxic T-cell function.34,35
Components of the innate immune system provide activating signals that can increase APC priming of T cells and immune-cell infiltration of the tumor microenvironment.4,36,37 Preclinical studies suggest that stimulating these components of innate immunity can increase the infiltration of cytotoxic T cells into noninflamed tumors.38,39
Noninflamed tumors also have low to no expression of chemokines.8 In the absence of chemokines, T-cell recruitment is impaired.8 Preclinical data suggest that stimulating chemokine production, such as by exposure to irradiation, can help restore cytotoxic T-cell recruitment and promote infiltration of the tumor.29,40
- Zhang Q, Zhu B, Li Y. Resolution of cancer-promoting inflammation: a new approach for anticancer therapy. Front Immunol. 2017;8:71. doi:10.3389/fimmu.2017.00071.
- Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782-795.
- Chen F, Zhuang X, Lin L, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45. doi:10.1186/s12916-015-0278-7.
- Spranger S, Gajewski TF. Tumor-intrinsic oncogene pathways mediating immune avoidance. Oncoimmunology. 2016;5(3):e1086862.
- Salmon H, Donnadieu E. Within tumors, interactions between T cells and tumor cells are impeded by the extracellular matrix. Oncoimmunology. 2012;1(6):992-994.
- Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321-330.
- Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22(8):1865-1874.
- Harlin H, Meng Y, Peterson AC, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077-3085.
- Spranger S, Bao R, Gajewski TFl. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231-235.
- Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti–PD-1 therapy. Clin Cancer Res. 2014;20(19)5064-5074.
- Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med. 2013;5(200):1-12. doi:10.1126/scitranslmed.3006504.
- Gajewski TF, Woo S-R, Zha Y, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol. 2013;25(2):268-276.
- Lam M, Tie J, Lee B, Desai J, Gibbs P, Tran B. Systemic inflammation – impact on tumor biology and outcomes in colorectal cancer. J Clin Cell Immunol. 2015;6:377. doi:10.4172/2155-9899.1000377.
- Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 2016;9:47. doi:10.1186/s13045-016-0277-y.
- Gajewski TF. The next hurdle in cancer immunotherapy: overcoming the non–T-cell–inflamed tumor microenvironment. Semin Oncol. 2015;42(4):663-671.
- Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;15(4):857-865.
- Zhang T, Somasundaram R, Berencsi K, et al. CXC chemokine ligand 12 (stromal cell-derived factor 1α) and CXCR4-dependent migration of CTLs toward melanoma cells in organotypic culture. J Immunol. 2005;174:5856-5863.
- Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 2010;16(4):399-403.
- Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-1544.
- Zhu H, Bengsch F, Syoronos N, et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep. 2016;16(11):2829-2837.
- Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, et al. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res. 2013;73(20):6264-6276.
- Pastori C, Daniel M, Penas C, et al. BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics. 2014;9(4):611-620.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1-S8. doi:10.1186/1710-1492-7-S1-S1.
- Fisk B, Blevins TL, Wharton JT, Ioannides CG. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med. 1995;181(6):2109-2117.
- Brezicka FT, Olling S, Nilsson O, et al. Immunohistological detection of fucosyl-Gm1 ganglioside in human lung cancer and normal tissues with monoclonal antibodies. Cancer Res. 1989;49(5):1300-1305.
- Brezicka FT, Holmgren J, Kalies I, Lindholm L. Tumor-cell killing by MAbs against fucosyl GM1, a ganglioside antigen associated with small-cell lung carcinoma. Int J Cancer. 1991;49(6):911-918.
- Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol. 2003;170(10):4905-4913.
- Anyaegbu CC, Lake RA, Heel K, Robinson BW, Fisher SA. Chemotherapy enhances cross-presentation of nuclear tumor antigens. PLoS ONE. 2014;9(9):e107894.
- Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Oncol. 2012;2:191.
- Adkins I, Fucikova J, Garg AD, Agostinis P, Špíšek R. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology. 2014;3(12):e968434.
- Liao Y-P, Wang C-C, Butterfield LH, et al. Ionizing radiation affects human MART-1 melanoma antigen processing and presentation by dendritic cells. J Immunol. 2004;173(4):2462-2469.
- Aurelian L. Oncolytic viruses as immunotherapy: progress and remaining challenges. Onco Targets Ther. 2016;9:2627-2637.
- Diaconu I, Cerullo V, Hirvinen ML, et al. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res. 2012;72(9):2327-2338.
- Steinman RM, Dhodapkar M. Active immunization against cancer with dendritic cells: the near future. Int J Cancer. 2001;94(4):459-473.
- Castle JC, Kreiter S, Diekmann J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72(5):1081-1091.
- Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830-842.
- Fuertes MB, Woo S-R, Burnett B, Fu Y-X, Gajewski TF. Type I IFN response and innate immune sensing of cancer. Trends Immunol. 2013;34(2):67-73.
- Demaria O, De gassart A, Coso S, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408-15413.
- Weiss JM, Guérin MV, Regnier F, et al. The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression. OncoImmunology. 2017;6(10):e1346765.
- Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res. 2002;62(5):1462-1470.