Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

Abstract

Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

Keywords: MSI; colorectal cancer; immune checkpoint inhibitors; immune escape; immune evasion; immune surveillance; microsatellite instability; mismatch repair deficiency.

Figure 1

Genetic and non-genetic mechanisms of immune evasion in MSI tumors. MSI tumors may trigger a prolific immune response in the presence of CPIs, since they generate more tumor-specific antigens than MSS tumors, thereby inducing the immune surveillance (green panel). However, MSI tumors can deceive the immune system through several evasion patterns: (a) alterations in the JAK-STAT pathway compromise the immune response and negatively regulate PD-L1 expression; (b) MMR-deficient and -proficient neoplastic cells in the same tumor might impede the prolific response to CPIs; (c) the Wnt/β catenin pathway in MSI tumors contributes to T cell exclusion, favoring the immune escape; (d) the loss of antigenicity, due to the acquisition of mutations in specific genes (e.g., MHC class I, B2M), compromises the opportunity to present tumor-derived antigens to the immune system; (e), immune suppression exerted by Tregs, MDSC, and peculiar cytokines like TGF-β and IL-10 leads to an inhibitory activity towards the immune cells with cytotoxic properties allowing tumor proliferation, vascularization, and metastasis formation. T cm (central memory T), T em (effector memory T). (f) tumors may lose the ability to be immunogenic mainly by the expression of inhibitory immune checkpoints (e.g., PD-L1, VISTA) that induce T cell “anergy”; several checkpoint molecules are detectable on antigen presenting cells other than on the tumor cell surface such as PD-L1, PD-L2, CD80, CD86, Galectin 9, and B7-H3. In addition, VISTA is also present on T cells. Created with BioRender.com.

Figure 2

Cytosolic DNA and cGas-STING pathway activation lead to a strong immune response triggered by an antigen- and INF-mediated activation of adaptive immune compartments. The contribution of neoantigens to tumor regression of MSI tumors upon CPIs is a matter of fact. However, recent findings demonstrated that cytosolic DNA accumulation occurs in MSI cancer cells [87]. As consequence of this biochemical process, the cGAS-STING pathway is activated, resulting in the induction of type I INF mediated response and leading to the secretion of pro-inflammatory cytokines that sustain and foster anti-tumor response through multiple mechanisms. These findings lead to emergent strategies to trigger an immune response and to enroll patients with a positive predictive response to CPIs (PD-1/PD-L1 and CTLA-4). Created with BioRender.com.