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 noninflammed to inflammed.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
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