Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity

Westcott, Peter MK, Muyas, Francesc, Hauck, Haley, Smith, Olivia C, Sacks, Nathan J, Ely, Zackery A, Jaeger, Alex M, Rideout, William M, Zhang, Daniel, Bhutkar, Arjun, Beytagh, Mary C, Canner, David A, Jaramillo, Grissel C, Bronson, Roderick T, Naranjo, Santiago, Jin, Abbey, Patten, JJ, Cruz, Amanda M, Shanahan, Sean-Luc, Cortes-Ciriano, Isidro, Jacks, Tyler (September 2023) Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity. Nature Genetics. ISSN 1061-4036

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Abstract

DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > cancer types > colorectal organism description > animal > mammal organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types
CSHL Authors:	Westcott, Peter
Communities:	CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	14 September 2023
Date Deposited:	21 Sep 2023 13:56
Last Modified:	30 Apr 2024 14:10
Related URLs:	Publisher PubMed
URI:	https://repository.cshl.edu/id/eprint/40934

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