Abstract
Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.
Highlights
Primary and recurrent solid cancers are often characterized by the intratumoral presence of various immune cells, T lymphocytes, B cells, NK cells, macrophages and other antigen presenting cells
The induction of CD8+ proliferation by CD137 signaling was dampened when a TCF1/β-catenin inhibitor, quercetin, was used [113]. These results show that CD137 signaling enhances the proliferation of activated CD8+ T cells by activating the TCF1/β-catenin axis via the PI3K/AKT/ERK pathway [113]
Inhibitory ligands, such as PD-L1, PD-L2 and CTLA-4, on cancer expression of inhibitory ligands. Inhibitory ligands, such as PD-L1, PD-L2 and CTLA-4, on cancer cells inhibit T cell proliferation and activation. This may result in escape from host anti-tumor cells inhibit T cell proliferation and activation
Summary
Primary and recurrent solid cancers are often characterized by the intratumoral presence of various immune cells, T lymphocytes, B cells, NK cells, macrophages and other antigen presenting cells. The presence of cytotoxic CD8+ TILs is highly prognostic for survival, indicating a functional role for these cells in the control of cancer progression. Mechanisms, including modes of immunosuppression, that allow the cancer cell to evade the immune system’s methods of recognition and destruction and proliferate Bearing this theory in mind and considering the growing promise of immunotherapeutic approaches for cancer treatment, there is great interest in identifying commonly-administered clinical agents, such as genome destabilizers, that are both cytotoxic to cancer cells and promote a cancer cell “elimination” through concurrent induction of immunogenic cancer cell death and inhibition of immune evasion mechanisms. We discuss the specific roles that conventional and non-conventional genomic destabilizers have on anti-tumor immunity and on inducing immune inhibitory or stimulatory molecules on cancer cells and how they may be best applied to promote the cancer cell elimination
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