License to kill: microsatellite instability and immune contexture

Abstract

Colorectal cancers (CRCs) with microsatellite instability (MSI) are due to a defect in the DNA mismatch repair (MMR) system resulting in an accumulation of frame-shift mutations. They are characterized by a tumor microenvironment richer in cytotoxic CD8 T-cells (CTLs) and a better prognosis compared to microsatellite stable (MSS) CRCs. The mechanisms by which defective MMR system may influence tumor-infiltrating immune cells and their impact on patient survival were still unclear. Thus, we performed a comprehensive analysis of MSI colorectal tumors. We found that the numbers of frame-shift mutations potentially resulting in neo-epitopes were positively correlated to the density of tumor infiltrating CD8 T-cells but were lower than expected at random. We also evidenced that MSI patients could naturally harbor CTLs targeting frame-shift mutation-derived antigens. This favors the hypothesis of an active immunosurveillance in MSI colorectal tumors leading to the genetic evidence of an immunoediting. To evaluate the link between MSI tumor immune contexture and prognosis, we took advantage of a standardized assay that we developed to quantify tumor-infiltrating T-cells, the Immunoscore. Multivariate analyses revealed an advantage of Immunoscore over MSI in predicting recurrence and survival. Our data suggests that the prognostic value of MSI could be attributed to major underlying differences of infiltrating immune cells. Immunotherapeutic treatments, that are more efficient in patients with a preexisting anti-tumor immunity, were approved in MSI patients following successful clinical trials. We suggest that the Immunoscore could be used not only for colorectal tumor prognosis but also for predicting responses to immunotherapies.

Homologous recombination deficiency is inversely correlated with microsatellite instability and identifies immunologically cold tumors in most cancer types

“…Over the last few years, many research efforts collectively led to an improved understanding of the immune cell context [15] in microsatellite unstable [16,17] and TMB-high [18] tumors, but studies comparing the immune cell composition in HRD-positive and -negative tumors are scarce. As a contribution to this research field, we comprehensively analyzed the association of HRD, MMRD/PRD, TMB, immune cell infiltration, and gene expression across 9,041 tumors of 32 solid cancer types.…”

Know thy immune self and non‐self: Proteomics informs on the expanse of self and non‐self, and how and where they arise

“…Some of the neoepitopes were generated from oncogenic driver mutations, not only lending to highly personalised anti‐cancer vaccination but to ‘off the shelf’ vaccines for individuals expressing HLA alleles of a supertype [ 327 , 328 , 329 , 330 ]. Neoepitopes are not only generated by snSNPs, but can emerge from frameshift mutations via dysregulated alternative splicing and exitron splicing events, and microsatellite instability, all of which are hallmarks of tumorigenesis [ 331 , 332 , 333 , 334 ]. We are just beginning to understand how a single amino acid alteration in a neoepitope beats immune tolerance to elicit an anti‐cancer response [ 335 ].…”

Immunoprofiling: An Encouraging Method for Predictive Factors Examination in Lung Cancer Patients Treated with Immunotherapy

“…The "hot" tumors, also described as highly inflammatory tumors, are thus defined by the presence of strong inflammation signals within the tissue, both in the form of inflammatory cell infiltration and high levels of pro-inflammatory cytokines (Figure 1). The tumor cells in "hot" tissue have undergone many mutations that create neoantigens, which should be recognized by the immune cells [45,46]. However, despite the fact that the neoplastic tissues are very intensively infiltrated by the immune system cells of specific and non-specific responses, the immune response in this type of tumor is extremely ineffective.…”

“…Firstly, the high percentages of cytotoxic T lymphocytes are widely described. However, they are functionally inactive [44][45][46]. In a mouse tumor model, at least four subpopulations of tumor-infiltrating T cytotoxic lymphocytes were labeled: (a) T lymphocytes with a functionally depleted cell phenotype with a very high expression of negative immune checkpoint molecules such as PD-1, LAG- ), and with a lack of any inhibitory checkpoint molecules [47,48].…”