Mismatch Repair Deficiency is Not Sufficient to Elicit Tumor Immunogenicity

Overview

Journal Nat Genet

Specialty Genetics

Date 2023 Sep 14

PMID 37709863

Authors

Peter M K Westcott

Francesc Muyas

Haley Hauck

Olivia C Smith

Nathan J Sacks

Zackery A Ely

Alex M Jaeger

William M Rideout 3rd

Daniel Zhang

Arjun Bhutkar

Mary C Beytagh

David A Canner

Grissel C Jaramillo

Roderick T Bronson

Santiago Naranjo

Abbey Jin

J J Patten

Amanda M Cruz

Sean-Luc Shanahan

Isidro Cortes-Ciriano

Tyler Jacks

Affiliations

Soon will be listed here.

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.

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