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SUSD2 suppresses CD8⁺ T cell antitumor immunity by targeting IL-2 receptor signaling.

ABSTRACT: Dysfunctional CD8⁺ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8⁺ T cell antitumor function. Susd2^-/- effector CD8⁺ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we found that SUSD2 interacted with interleukin (IL)-2 receptor α through sushi domain-dependent protein interactions and that this interaction suppressed the binding of IL-2, an essential cytokine for the effector functions of CD8⁺ T cells, to IL-2 receptor α. SUSD2 was not expressed on regulatory CD4⁺ T cells and did not affect the inhibitory function of these cells. Adoptive transfer of Susd2^-/- chimeric antigen receptor T cells induced a robust antitumor response in mice, highlighting the potential of SUSD2 as an immunotherapy target for cancer.

SUBMITTER: Zhao B

PROVIDER: S-EPMC9669207 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.

Zhao Bao B Gong Weipeng W Ma Anjun A Chen Jianwen J Velegraki Maria M Dong Hong H Liu Zihao Z Wang Lingling L Okimoto Tamio T Jones Devin M DM Lei Yu L YL Long Meixiao M Oestreich Kenneth J KJ Ma Qin Q Xin Gang G Carbone David P DP He Kai K Li Zihai Z Wen Haitao H

Nature immunology 20221020 11

Dysfunctional CD8+ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8+ T cell antitumor function. Susd2-/- effector CD8+ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assa ...[more]

PMID: 36266363

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Project description:BackgroundVariated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1).MethodsSeveral tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined.ResultsAcute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3-, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6-Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase.ConclusionsAbnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.

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SUSD2 suppresses CD8⁺ T cell antitumor immunity by targeting IL-2 receptor signaling.

Publications

SUSD2 suppresses CD8<sup>+</sup> T cell antitumor immunity by targeting IL-2 receptor signaling.

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