Antitumor immunity in dMMR colorectal cancers requires interferon-induced CCL5 and CXCL10

Abstract

Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) are heavily infiltrated by CD8+ tumor infiltrating lymphocytes (TILs) and are associated with a better prognosis than the majority of CRCs. The immunogenicity of dMMR CRCs is commonly attributed to abundant neoantigen generation due to their extreme genomic instability. However, lack of neoantigenic overlap between these and other CRCs necessitates study of antigen-independent mechanisms of immune activation by dMMR CRCs in order identify therapeutic strategies for treating MMR proficient CRCs. We show here using organoid cocultures and orthotopic models that a critical component of dMMR CRCs immunogenicity is the activation and recruitment of systemic CD8+ T cells into the tumor epithelium by overexpression of the chemokines CCL5 and CXCL10. This is dependent on endogenous activation of the cGAS/STING and IFN signaling pathways by the damaged DNA in dMMR CRCs. These signaling pathways remain sensitive to exogenous stimulation in other CRCs, identifying an attractive therapeutic avenue for increasing TIL infiltration into normally immune resistant CRC subtypes. We have thus identified a key neoantigen-independent mechanism that underlies the ability for dMMR CRCs to recruit TILs into the tumor epithelium. Given that TIL recruitment is a prerequisite for effective tumor killing either by the endogenous immune system or in the context of immunotherapies, treatments that activate IFN-induced chemokine-production by tumor cells promise to improve the prognosis of patients with many different CRC subsets. Statement of SignificanceA critical component of antitumor immunity in dMMR CRCs is their ability to recruit T cells into the tumor epithelium as a prerequisite to tumor cell killing. This occurs because their extensive genomic instability leads to endogenous activation of cGAS/STING and overexpression of CCL5 and CXCL10.