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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.

SUBMITTER: Lu C

PROVIDER: S-EPMC6589175 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Lu Chunwan C Klement John D JD Ibrahim Mohammed L ML Xiao Wei W Redd Priscilla S PS Nayak-Kapoor Asha A Zhou Gang G Liu Kebin K

Journal for immunotherapy of cancer 20190622 1

<h4>Background</h4>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.<h4>Methods</h4>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 wi ...[more]

PMID: 31228946

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Project description:BackgroundEsophageal cancer, especially esophageal squamous cell carcinoma (ESCC), is a common malignant tumor of the digestive tract. Bufalin is an effective anti-tumor compound. However, little is known about the regulatory mechanisms of Bufalin in ESCC. To investigate the effect and molecular mechanism of Bufalin on the proliferation, migration and invasion of ESCC cells will provide a more reliable basis for the application of Bufalin in clinical tumor therapy.MethodsFirst, the half-inhibitory concentration (IC50) of Bufalin was evaluated by Cell Counting Kit-8 (CCK-8) assays. In vitro, the effects of Bufalin on the proliferation of the ECA109 cells was measured using CCK-8 and 5-ethynyl-2'-deoxyuridine assays. Wound-healing and transwell assays were used to evaluate the effects of Bufalin on the migration and invasion of the ECA109 cells. Further, to determine the mechanisms underlying the Bufalin-mediated suppression of cell progression in ESCC, total RNA was extracted from negative control (NC) and Bufalin treated cells to perform RNA-sequencing (RNA-seq) to screen for abnormally expressed genes. In vivo, the ECA 109 cells were subcutaneously injected into BALB/c nude mice to determine the effects of Bufalin on tumor cell proliferation. The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) protein expression levels in the ECA109 cells were detected by Western blot.ResultsThe CCK-8 assays showed that the IC50 of Bufalin was 200 nM. The proliferation, migration, and invasion ability of the ECA109 cells was significantly inhibited in the Bufalin group in a concentration-dependent manner. In vivo, the Xenograft tumor model showed that Bufalin decreased the tumor volume and weight of the subcutaneous tumors. The RNA-seq results showed that the expression of PIAS3 was upregulated in the Bufalin group. Additionally, down-regulation of PIAS3 decreased the inhibition of STAT3, thereby increasing p-STAT3 expression. Finally, PIAS3 knockdown reversed the inhibitory effects of Bufalin on the proliferation, migration, and invasion of the ECA109 cells.ConclusionsBufalin may inhibit the proliferation, migration, and invasion of the ECA109 cells through the PIAS3/STAT3 signaling pathway.

Dataset Information

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

Publications

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

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