Immune escape and resistance to immunotherapy in mismatch repair deficient tumors

Abstract

Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient (MMRd) cancer. Due to an inability to repair DNA, MMRd tumors present with genomic instability in microsatellite regions (MS). Tumors with high MS instability (MSI-H) are characterized by an increased frequency of insertion/deletions (indels) that can encode novel neoantigens if they occur in coding regions. The high tumor antigen burden for MMRd cancers is accompanied by an inflamed tumor microenvironment (TME) that contributes to the clinical effectiveness of anti-PD-1 therapy in this patient population. However, between 40 and 70% of MMRd cancer patients do not respond to treatment with PD-1 blockade, suggesting that tumor-intrinsic and -extrinsic resistance mechanisms may affect the success of checkpoint blockade. Immune evasion mechanisms that occur during early tumorigenesis and persist through cancer development may provide a window into resistance pathways that limit the effectiveness of anti-PD-1 therapy. Here, we review the mechanisms of immune escape in MMRd tumors during development and checkpoint blockade treatment, including T cell dysregulation and myeloid cell-mediated immunosuppression in the TME. Finally, we discuss the development of new therapeutic approaches to tackle resistance in MMRd tumors, including cancer vaccines, therapies targeting immunosuppressive myeloid programs, and immune checkpoint combination strategies.

Keywords: MMRd; MSI-H; PD1 (programmed cell death protein 1); colorectal cancer; immunotherapy; microsatellite unstable (high); myeloid cells; resistance.

Figure 1

Mechanisms of mismatch repair deficiency leading to cancer development (A) Mismatch repair deficiency is characterized by mutations in or epigenetic inactivation of MMR genes (MLH1, MSH2, PMS2 and MSH6). Normally, proteins encoded by MMR genes detect errors in replication and recruit proteins encoded by MLH and PMS genes. This complex recruits the PCNA/exonuclease complex that excises the mismatch and repairs the DNA through insertion of correct bases. Then, Pol δ is recruited for both leading and lagging strand synthesis, and the ligases catalyze the joining of repaired DNA fragments. (B, C) Accumulation of mutations that are not repaired following MMR deficiency leads to microsatellite extension or shortening through base-pair or three-nucleotide insertion/deletion in microsatellite repeated sequences. This leads to the production of neoantigens if the altered transcript is a coding one. (Created with BioRender.com).

Figure 2

MMRd triggers T cell response through neoantigen production and the cGAS-STING pathway. Cytosolic DNA is sensed by the cGAS-STING pathways causing increased expression of IL-6, TNF, and type-I interferon which augments APC activation and T cell recruitment. These infiltrating T cells recognize frameshift-neoantigens encoded by insertion/deletion events at microsatellite loci. (Created with BioRender.com).

Figure 3

Postulated mechanisms by which MSI-H tumors evade immune recognition during development and following ICB. (A) LS-associated polyps initially have low mutational and neoantigen burden. Immunoediting of quality (immunogenic) neoantigens with low and/or subclonal expression and impaired antigen presentation may lead to immune evasion in developing tumors. (B) LS associated polyps display an immune activation profile characterized by CD4 T cells, proinflammatory cytokines (TNF, IL-12), and CTLA-4, LAG3 and PD-L1 checkpoints. They progressively develop additional mutations and high TMB, which is characterized by T cells entering an exhaustion state. It may also involve an IFN-induced expression of HLA-E that inhibits CD8+ T cells and NK cells via the NKG2A/CD94 receptor. (C, D) MSI-H tumors can develop strong anti-tumor immune responses as well as developing immune suppressive inflammatory hubs that compromise anti-tumor immunity (47). In human MSI-H tumors, an inflammatory hub populated by inflammatory Tregs (C), MMP-expressing CAFs (D), monocytes, and neutrophils may further increase immune escape during MSI-H tumor development, promoting tumor angiogenesis and tissue remodeling (47). (Created with BioRender.com).

Figure 4

Strategies to overcome immune resistance of MSI-H tumors These strategies may include ICB combinations (anti-PD-1, anti-CTLA-4 to target Tregs, anti-LAG3, and others), targeting myeloid cells and inflammatory pathways and targeting myeloid immunosuppressive programs (anti-Ly6C to target neutrophils, anti-Trem2 to target macrophages, anti-IL-4 and IL-13 to target mregDCs, anti-inflammatory drugs to limit inflammatory hubs formation). It may act together with preventive strategies such as MSI-H cancer vaccines (shared frameshift peptide vaccines, ACT, DC vaccines, mRNA or viral vector vaccines). (Created with BioRender.com).