Tumor Cells Can Evade and Suppress Immune Activity
In order to survive and grow, tumor cells evolve to outsmart the stages of the antitumor immune response. They aim to evade or suppress the body’s natural ability to fight cancer. 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.1 Depending upon their degree of immune cell infiltration, tumors are defined on a range from inflamed to noninflamed.1
Noninflamed tumors are characterized by the poor presence of immune cells in the tumor microenvironment, most notably cytotoxic T cells.1,2 Noninflamed tumors can have an impaired ability to present tumor antigens to T cells and to direct tumor-specific T cells to the tumor.3 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.2 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.4,5
Inflamed tumors are marked by the presence of immune cells.1,2 A growing body of evidence suggests the existence of a T-cell-inflamed tumor microenvironment in a major subset of advanced solid tumors.6 These cancers have a high mutational load and produce a high number of tumor antigens, which can facilitate recruitment of diverse cytotoxic T cells.1,7,8 Unlike noninflamed tumors, antigen presentation as well as T-cell activation are active processes in inflamed tumors.9 Expression of chemokines allows for infiltration of activated cytotoxic T cells to the tumor site.2,10,11 To escape detection and destruction by these immune effector cells, tumor cells may increase their expression of inhibitory proteins.5,12 One mechanism for achieving this is to upregulate factors such as the bromodomain and extra-terminal (BET) family of proteins that regulate the expression of inhibitory proteins.13-15 These inhibitory mechanisms can prevent cytotoxic T cells from eliminating tumor cells—allowing tumor cells and immune cells to coexist within the tumor microenvironment.5,9
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 are required for the initiation of an adaptive antitumor immune response. In addition to mutated proteins specific to tumor cells, proteins that are highly expressed on tumor cells, such as Fucosyl-GM1, may also serve as tumor antigens with the potential to activate cytotoxic T cells.16,17 Preclinical data suggest that promoting tumor cell death in order to stimulate the release of tumor antigens may help to initiate an immune response.18
Noninflamed tumors also have low to no expression of chemokines.2 In the absence of chemokines, T-cell recruitment is impaired.2 Preclinical data suggests that promotion of chemokine production can help restore cytotoxic T-cell migration.19,20
References
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