Mowat et al. observed that in colorectal cancers (CRCs), chemokines CCL5 and CXCL10 were more highly expressed in tumors with loss of DNA repair function (dMMR CRCs) than in tumors with genome instability caused by a suppressor gene deficiency (CIN CRCs). Analyses revealed endogenous activation of type I IFN signaling in a murine dMMR line. Compared to a CIN line, the dMMR cell line: a) expressed higher levels of chemokines CCL5 and CXCL10 (capable of in vitro CD8+ T cell chemotaxis), and b) enhanced the in vivo recruitment and activation of CD8+ TILs, and increased their differentiation towards a tissue-resident memory phenotype.
Contributed by Margot O’Toole
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.
Author Info: (1) Department of Oncology, University of Alberta, Edmonton, Canada. (2) Department of Oncology, University of Alberta, Edmonton, Canada. (3) Department of Oncology, University of
Author Info: (1) Department of Oncology, University of Alberta, Edmonton, Canada. (2) Department of Oncology, University of Alberta, Edmonton, Canada. (3) Department of Oncology, University of Alberta, Edmonton, Canada. (4) Department of Surgery, Royal Alexandra Hospital, Edmonton, Canada. (5) Department of Oncology, University of Alberta, Edmonton, Canada. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
