Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity

Abstract DNA mismatch repair deficiency (MMRd) is associated with high tumor mutational burden (TMB), increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy1. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While cell line transplant models of MMRd have reinforced the importance of TMB in immune response2,3, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with ablation of MMR via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not increase T cell infiltration or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity. Studies in immune deficient animals further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating heterogeneity. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

Download Full-text

Mismatch repair deficiency is not sufficient to increase tumor immunogenicity

10.1101/2021.08.24.457572 ◽

2021 ◽

Author(s):

Peter M K Westcott ◽

Francesc Muyas ◽

Olivia Smith ◽

Haley Hauck ◽

Nathan J Sacks ◽

...

Keyword(s):

Mismatch Repair ◽

Human Cancer ◽

Tumor Cell Line ◽

Immune Checkpoint Blockade ◽

Mismatch Repair Deficiency ◽

Dna Mismatch ◽

T Cell Infiltration ◽

Repair Deficiency ◽

Tumor Mutational Burden

AbstractDNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of MMRd have reinforced the importance of TMB in immune response, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not result in increased immunogenicity or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity (ITH). Studies in animals depleted of T cells further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

Download Full-text

Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review

Journal of Clinical Medicine ◽

10.3390/jcm9061741 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1741 ◽

Cited By ~ 2

Author(s):

Lena Bohaumilitzky ◽

Magnus von Knebel Doeberitz ◽

Matthias Kloor ◽

Aysel Ahadova

Keyword(s):

T Cell ◽

Immune Responses ◽

Mismatch Repair ◽

Science Studies ◽

Immune Checkpoint Blockade ◽

Cell Infiltration ◽

Dna Mismatch ◽

T Cell Infiltration ◽

Hereditary Tumors ◽

Mmr Deficiency

Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors.

Download Full-text