Intrinsic RIG-I restrains STAT5 activation to modulate antitumor activity of CD8+ T cells
Xinyi Jiang, … , Jiang Zhu, Hui Yang
Xinyi Jiang, … , Jiang Zhu, Hui Yang
Published March 16, 2023
Citation Information: J Clin Invest. 2023;133(9):e160790. https://doi.org/10.1172/JCI160790.
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Research Article Immunology Oncology

Intrinsic RIG-I restrains STAT5 activation to modulate antitumor activity of CD8+ T cells

Abstract

Antitumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in the tumor microenvironment, yet, the exact mechanisms remain incompletely defined. Here, we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that the tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells. Mechanistically, T cell activation–induced RIG-I upregulation restrained STAT5 activation via competitive sequestering of HSP90. In accordance with this, the frequency of RIG-I+ tumor-infiltrating CD8+ T cells in human colon cancer positively correlated with attenuated survival and effector signatures of CD8+ T cells as well as poor prognosis. Collectively, these results implicate RIG-I as a potentially druggable factor for improving CD8+ T cell–based tumor immunotherapy.

Authors

Xinyi Jiang, Jian Lin, Chengfang Shangguan, Xiaoyao Wang, Bin Xiang, Juan Chen, Hezhou Guo, Wu Zhang, Jun Zhang, Yan Shi, Jiang Zhu, Hui Yang

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Figure 5

Rig-I deficiency enhances antitumor activity of transferred antigen-specific CD8+ T cells.

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Rig-I deficiency enhances antitumor activity of transferred antigen-spe...
(A) The presentation of OVA-derived SIINFEKL peptide by H-2Kb in MC38 or puromycin-screened MC38-OVA cells was analyzed by flow cytometry. (B and C) Splenic CD8+ T cells from OT-I mice were retrovirally transfected with control-GFP (vector) or Rig-I-shRNA-GFP (Rig-I-shRNA). The expression of GFP was confirmed by flow cytometry (B) and RIG-I protein level of GFP+ cells was analyzed by Western blotting (C). (D) Vector or Rig-I-shRNA-2–transfected CD8+ T cells from spleens of OT-I mice were cocultured with MC38-OVA cells at indicated E-to-T ratios and killing efficiency was analyzed by flow cytometry. (E) 2 × 105 MC38-OVA tumor cells were s.c. inoculated in WT C57 mice. CD8+ T cells isolated from the spleens of OT-I mice were retrovirally transfected with vector or Rig-I-shRNA-2, and a total of 2 × 106 infected OT-I cells were transferred into mice bearing MC38-OVA tumor (n = 5 per group) when the tumor was visible. Tumor growth curve and representative picture of tumors retrieved from mice on day 34 are shown. (F and G) Tumors were extracted 34 days later after tumor inoculation for tumor-infiltrating CD8+tetramer+ T cell analysis. CD8+tetramer+ T cell number was counted (F) and the percentages of IFN-γ+ or CD107a+ cells (G) of antigen-specific CD8+ T cells were analyzed by flow cytometry. Data are representative of 2 independent experiments and expressed as mean ± SEM. *P < 0.05, ****P < 0.0001, by 2-way ANOVA (D and E) or unpaired Student’s t test (F and G).