The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy

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.

Assessment of the expression of the immune checkpoint molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 across different cancers in relation to treatment response, tumor‐infiltrating immune cells and survival

“…Unlike in ovarian cancer patients, lung cancer patients with a high level of PD‐1 had relatively poor OS and FPS after chemotherapy treatment, which implied that a combination of chemotherapy and PD‐1 blockade might produce unexpected benefits. It has already been proven that chemotherapy can change the expression level of PD‐1, but the direction of this change depends on the cell line and chemotherapeutic agent . Moreover, a recent study investigated the expression of PD‐1 and PD‐L1 before and after platinum‐based neoadjuvant chemotherapy in lung cancer patients and found that only PD‐L1 expression decreased significantly after chemotherapy .…”

Neoadjuvant chemoradiotherapy of pancreatic cancer induces a favorable immunogenic tumor microenvironment associated with increased major histocompatibility complex class I‐related chain A/B expression

“…4,16 DAMPs expressed in the tumor cells induced by the destructive effects of chemotherapy or radiotherapy can be followed by antigen-specific cytotoxic T cell killing. 17,18 In the present study, the combination of adjuvant chemotherapy and radiotherapy contributed to immunogenicity.…”

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

“…In cases of DNA hypermethylation, therapy with DNA methyltransferase inhibitors (DNMTi) such as azacytidine and decitabine restores the expression of HLA class I derived peptide complex [ 263 ]. Azacytidine increased the transcription of APM genes and HLA class I molecule expression in lung carcinoma and melanoma cells [ 246 , 247 ]. Guadecitabine, a novel DNMTi, significantly up-regulated both basal and IFN-γ-dependent expression of HLA class I derived peptide complex in breast cancer cells [ 248 ].…”