Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN–driven CCL5 and CXCL10

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.

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

“…The aberrant DNA fragments are spilled over from the nucleus during DNA replication and recognized by cGAS-STING as "non-self" inducing Type I interferon and inflammatory NFkB responses (74,75). In agreement with this hypothesis, recent study by Mowat et al showed that cGAS-STING driven type I interferon signaling is required for CXCL10/ CCL5-dependent T cell recruitment to dMMR tumor site (76). Both "frameshift-neoantigen" and "DNA instability" models are instructive and complementary in explaining the origins of the dMMR tumor immunogenicity (Figure 1C).…”

Identification of Potential Prognostic and Predictive Immunological Biomarkers in Patients with Stage I and Stage III Non-Small Cell Lung Cancer (NSCLC): A Prospective Exploratory Study

“…Treatment-driven ICD involves the activation of a cancer cell-intrinsic type I IFN response and consequent secretion of CXCL10 that mediates chemotactic effects of activating immune cells, including cytotoxic CD8+ T-cells and NK-cells, into the tumor microenvironment [ 19 , 45 ]. Given that CXCL10 expression by tumors is associated with effective anti-tumor immunity and CD8+ T-cell regulation [ 46 ], we did not expect to observe a negative correlation between circulating levels of CXCL10 and PFS in patients with stage I NSCLC treated with SBRT. However, in line with our observations, previous studies have also shown similar results in patients with other cancer types; high levels of CXCL10 were correlated with tumor recurrence or even a lower survival [ 47 , 48 , 49 ].…”

SHP-2 and canonical PD-1: SHP-2 axis regulate myeloid cell differentiation, anti-tumor responses and innate immune memory

“…Although it was initially thought that type I IFNs exert direct anticancer effects by activating IFNAR signaling in malignant cells hence inhibiting cell cycle progression 100 , promoting terminal differentiation 101 or inducing apoptosis 102 , it is becoming increasingly clear that type I IFNs mainly function by stimulating anticancer immune responses via autocrine or paracrine signaling circuits by IFN-stimulated genes 103,104 . These have an instrumental role in the production of IFN-dependent chemokines that lead to preferential recruitment and retention of systemic CD8 + T cells in the tumor, an outcome that can be recapitulated by treatment with type I IFN or DNA damaging chemo-and radiotherapies 105 . In our work, we found that SHP-2 deficient TAMs displayed a significant increase of STING (Supplementary Table 2), TLR signaling (Fig.…”