Immunotherapy for colorectal cancer: insight from inherited genetics

Abstract

Immunotherapy shows efficacy for multiple cancer types and potential for expanded use. However, current immune checkpoint inhibitors (ICIs) are ineffective against microsatellite-stable colorectal cancer (CRC), which is more commonly diagnosed. Immunotherapy strategies for non-responsive CRC, including new targets and new combination therapies, are being tested to address this need. Importantly, a subset of inherited germline genetic variants associated with CRC risk are predicted to regulate genes with immune functions, including genes related to existing ICIs, as well as new potential targets in the major histocompatibility complex (MHC) region and immunoregulatory cytokines. We review discoveries in the inherited genetics of CRC related to the immune system and draw connections with ongoing developments and emerging immunotherapy targets.

Keywords: GWAS; colorectal cancer; immune checkpoint inhibitor; immunotherapy; pharmacogenomics.

Figure 1, Key Figure:. Variants in immune-related genes associated with CRC.

Variants (indicated by rsIDs) associated with CRC risk or survival from GWAS and/or candidate gene studies and their corresponding immune gene-encoding proteins and main cell types are shown. Cell types include tumor cells (yellow), APCs (blue, branching), macrophages (pink), NK and effector T cells (purple), neutrophils (gray), MDSCs (green), and Th17 cells (blue, round), while interactions involve cytokines (circles), receptors (chevrons) and cell surface proteins (triangles). (i) Variants on the left (yellow background) are genes associated with pro-inflammatory cytokines (IL-33, IL-1α, IL-1β, CXCR1, CXCR2, IL-6, IL-17F, IL-17A) downstream effectors of inflammation (TOX, SH2B3), or pro-tumorigenic interactions between tumor and NK and T cells (CTLA4, PD-1, PD-L1, HLA-G, KIR2DS5 and KIR2DS3) (ii) Genes associated with anti-tumor effectors are listed on the right (green background). Abbreviations: CRC, colorectal cancer; GWAS, Genome-wide association study; APCs, antigen presenting cells; NK, Natural Killer; MDSC, myeloid-derived suppressor cell; Th17, T-helper 17. *genes with mixed or uncertain effects