Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes

Abstract

Background Type I interferons (IFN-I) have recently emerged as key regulators of tumor response to chemotherapy and immunotherapy. However, IFN-I function in cytotoxic T lymphocytes (CTLs) in the tumor microenvironment is largely unknown. Methods Tumor tissues and CTLs of human colorectal cancer patients were analyzed for interferon (alpha and beta) receptor 1 (IFNAR1) expression. IFNAR1 knock out (IFNAR-KO), mixed wild type (WT) and IFNAR1-KO bone marrow chimera mice, and mice with IFNAR1 deficiency only in T cells (IFNAR1-TKO) were used to determine IFN-I function in T cells in tumor suppression. IFN-I target genes in tumor-infiltrating and antigen-specific CTLs were identified and functionally analyzed. Results IFNAR1 expression level is significantly lower in human colorectal carcinoma tissue than in normal colon tissue. IFNAR1 protein is also significantly lower on CTLs from colorectal cancer patients than those from healthy donors. Although IFNAR1-KO mice exhibited increased susceptibility to methylcholanthrene-induced sarcoma, IFNAR1-sufficient tumors also grow significantly faster in IFNAR1-KO mice and in mice with IFNAR1 deficiency only in T cells (IFNAR1-TKO), suggesting that IFN-I functions in T cells to enhance host cancer immunosurveillance. Strikingly, tumor-infiltrating CTL levels are similar between tumor-bearing WT and IFNAR1-KO mice. Competitive reconstitution of mixed WT and IFNAR1-KO bone marrow chimera mice further determined that IFNAR1-deficient naïve CTLs exhibit no deficiency in response to vaccination to generate antigen-specific CTLs as compared to WT CTLs. Gene expression profiling determined that Gzmb expression is down-regulated in tumor-infiltrating CTLs of IFNAR1-KO mice as compared to WT mice, and in antigen-specific IFNAR1-KO CTLs as compared to WT CTLs in vivo. Mechanistically, we determined that IFN-I activates STAT3 that binds to the Gzmb promoter to activate Gzmb transcription in CTLs. Conclusion IFN-I induces STAT3 activation to activate Gzmb expression to enhance CTL effector function to suppress tumor development. Human colorectal carcinoma may use down-regulation of IFNAR1 on CTLs to suppress CTL effector function to evade host cancer immunosurveillance. Electronic supplementary material The online version of this article (10.1186/s40425-019-0635-8) contains supplementary material, which is available to authorized users.

Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection

“…Although the role of IFN-I is well established for maximal virus-specific T cell expansion, survival, and cytolytic effector function, the complex molecular pathways and ISGs that promote these effects are diverse and are yet to be fully characterized (3). IFN-Is directly drive factors required for effector differentiation through STAT signaling, such as CD25, Tbet, GranzymeB and IFNγ (35)(36)(37)(38)(39). At the onset of chronic viral infection, this results in the promotion of shorter lived GranzymeB+ effector CD8 T cell differentiation at the expense of more long-lived TCF1+ memory-like cells (35).…”

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

“…The increasing complexity and context-specificity of JAK-STAT signaling continues to be revealed through preclinical studies that have often yielded conflicting and surprising results. Such findings include the loss of effector cell function and increased metastasis in response to STAT3 inhibition [3], type I IFN-driven STAT3-dependent induction of cytotoxicity in tumor-infiltrating T cells to suppress tumor formation [233], and IFNAR1:STAT1-dependent Treg expansion and the production of IL-10 in the TME [234]. The cross-regulation and duplicity of JAK-STAT pathway mediators means that modulating a single target might not give rise to predicted phenotypical outcomes and may, in fact, generate undesired and often detrimental responses, as seen with the indiscriminate use of JAKinibs.…”

Investigation of Immune‐related Makers Associated with Tumor-infiltrating T Cells in Ovarian Cancer

“…It is reported that GZMB is used by activated cytotoxic T lymphocytes to induce apoptosis of target cells (35). In tumor-in ltrating cytotoxic T lymphocytes, type I interferon is found to inhibit tumor growth by inducing STAT3 activation to promote the expression of GZMB (36). Moreover, Prizment et al has demonstrated that GZMB expression is correlated with the improved survival of patients with colorectal cancer and might be used as a useful prognostic factor (37).…”