Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

Abstract

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

Keywords: epigenetics; immunotherapy; melanoma; non-small-cell lung cancer; predictor; resistance; stroma.

Figure 1

Representative mechanisms of resistance to anti-PD-1 immune checkpoint blockade. (A) A low epitope load in the tumor cells normally drives to a minimal immune reinvigoration due to a lower capacity of antigen presenting cells (APC) to present antigen to T cells (low priming) and a lower cytotoxic T cell recognition of the tumor cell antigen. (B) Loss-of-function mutations of Janus kinase (JAKs) desensitize the T cells to the IFN-γ exposure and dramatically decrease the expression level of PD-L1 through lack of activation of the transcription factor STAT. This decrease in PD-L1 leads to both primary and acquired resistance of PD-1 blockade therapy, given that the reinvigoration capacity of T cell through reactivation of the PD-1/PD-L1 axis is abrogated. (C) Deleterious mutations in the gene encoding β2 microglobulin (an MHC class I subunit) lead to loss of antigen presentation, producing resistance to anti-PD-1 drugs. (D) The propensity of the tumor-related PD-1 macrophages to take up anti-PD-1 monoclonal antibodies causes the capture of the anti-PD-1 antibody even from the surface of the PD-1⁺CD8⁺ T cells that already bound the drug. This impedes or reverts the anti-PD-1/PD-1 interaction at the cytotoxic T cell provoking resistance to the treatment. (E) In the “escape” phase of the tumor immunoediting, when the tumor is clinically manifested, tolerogenic dendritic cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages secrete indoleamine-2,3-dioxygenase (IDO), which decreases tryptophan and increases kynurenine. These molecules inhibit effector T cells and NK functions and stimulate regulatory T cells, provoking immunosuppression and enhancing the tolerogenicity of macrophages and dendritic cells. IDO1 also enhances the expansion and activation of MDSCs. All previous alterations suppress the activity of anti-tumor effector T cells.