A CD4+ T lymphocyte–specific TCR/GSDMD/IL-2 axis facilitates antitumor immunity
Yihan Yao, Lingling Wang, Weiqin Jiang, Ning Wang, Mengjie Li, Wenlong Lin, Ting Zhang, Wanqiang Sheng, Xiaojian Wang
Yihan Yao, Lingling Wang, Weiqin Jiang, Ning Wang, Mengjie Li, Wenlong Lin, Ting Zhang, Wanqiang Sheng, Xiaojian Wang
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Research Article Immunology Oncology

A CD4+ T lymphocyte–specific TCR/GSDMD/IL-2 axis facilitates antitumor immunity

Abstract

Gasdermin (GSDM) family proteins mediate tumor pyroptosis and impact cancer progression, but other than that, their involvement in the tumor immune microenvironment remains largely unknown. Here, we show that activation of GSDMD in human tumor specimens mainly occurs in tumor-infiltrating leukocytes. Significantly, GSDMD deficiency or its inactivation in CD4+ T cells disabled CD8+ T cell–mediated antitumor immunity and caused tumor outgrowth in mice. Further study uncovered that, via inducing IL-2 production, GSDMD was required for CD4+ T cells to provide help to CD8+ T cell function. Mechanistically, GSDMD was cleaved by TCR stimulation–activated caspase-8 to form GSDMD-N pores, which enhanced Ca2+ influx for IL-2 induction. Moreover, GSDMD activation and function were conserved in human CD4+ T cells and associated with favorable prognosis and improved response to anti–PD-1 immunotherapy in colonic and pancreatic cancer. We believe this study identifies a new nonpyroptotic role of GSDMD in tumor immunity, proposing GSDMD as a potential target for cancer immunotherapy.

Authors

Yihan Yao, Lingling Wang, Weiqin Jiang, Ning Wang, Mengjie Li, Wenlong Lin, Ting Zhang, Wanqiang Sheng, Xiaojian Wang

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Figure 1

GSDMD deficiency in immune cells promotes tumor growth.

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GSDMD deficiency in immune cells promotes tumor growth. (A and B) Immuno...
(A and B) Immunofluorescence staining of GSDMD-N (red) and CD45 (green) in tumor tissues from colorectal or pancreatic cancer patients (A). The percentages of GSDMD-N+ cells among CD45+ cells were quantified from 5 independent fields of view within CRC and PAAD tumor tissues (B). Scale bars: 10 μm. The white arrowheads indicate GSDMD-N– and CD45-coexpressing cells. CRC, colorectal cancer; PAAD, pancreatic adenocarcinoma. (C and D) Tumor growth curves (left) and tumor weight (right) of WT and Gsdmd–/– mice subcutaneously inoculated with MC38 (C, n = 10 per group) or KPC tumor cells (D, n = 7 per group). (E and F) Tumor growth curves (left) and tumor weight (right) of Gsdmdfl/fl and Gsdmdfl/fl Vavcre mice subcutaneously inoculated with MC38 (E, n = 6–8 per group) or KPC tumor cells (F, n = 4–5 per group). (G and H) Tumor growth curves (left) and tumor weight (right) of WT mice subcutaneously inoculated with MC38 (G, n = 9 per group) or KPC tumor cells (H, n = 7–8 per group) and treated with DMSO or disulfiram (DSF). (I) Tumor growth curves (left) and tumor weight (right) of WT and Gsdmd–/– mice inoculated with Gsdmd–/– MC38 tumor cells and treated with DMSO or DSF (n = 7–8 per group). Data are presented as mean ± SEM (B–I) and are representative of at least 2 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant; as determined by unpaired 2-tailed Student’s t tests for tumor weights in C–H and 1-way ANOVA for tumor weights in I or 2-way ANOVA for tumor growth curves.