Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN-driven CCL5 and CXCL10.
J Exp Med, 2021/09/06;218(9)
Mowat C[1], Mosley SR[1], Namdar A[1], Schiller D[2], Baker K[1, 3]
Affiliations
PMID: 34297038DOI: 10.1084/jem.20210108
Impact factor: 17.579
Abstract
Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.
MeSH terms
Animals; CD8-Positive T-Lymphocytes; Chemokine CCL5; Chemokine CXCL10; Colonic Neoplasms; Cytotoxicity Tests, Immunologic; DNA Mismatch Repair; Female; Genomic Instability; Humans; Interferon Type I; Lymphocytes, Tumor-Infiltrating; Male; Mice, Inbred C57BL; MutL Protein Homolog 1; Mice
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