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 4

Intrinsic Rig-I deficiency boosts antitumor activity of adoptively transferred CD8+ T cells.

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Intrinsic Rig-I deficiency boosts antitumor activity of adoptively trans...
(A and B) 2 × 106 Naive CD8+ T cells from spleens of Rig-I+/+ or Rig-I–/– mice were i.v. transfused into Rag1–/– mice. Saline was used as a vehicle control. 2 × 105 MC38 cells were s.c. inoculated 1 day after T cell injection and tumor volume was measured on days 10, 13, 15, 19, and 21 (n = 6 per group). Experimental design (A) and tumor growth curve (B) are shown. (C) CD45+CD8+ cell number was counted using flow cytometry. (D and E) Annexin V, IFN-γ, and CD107a were detected by flow cytometry. The percentage of Annexin V+ cells (D) and IFN-γ+ or CD107a+ cells (E) in CD45+CD8+ cells are shown. (F and G) Immunofluorescence staining of tumor tissue was performed to detect the nuclei (DAPI; blue), CD8 (green) and granzyme B (red). 10 random fields of view for each group were analyzed. Representative images (F) and combined plots (G) of the percentages of GZMB+CD8+ T cells were shown. Data are representative of 2 independent experiments and expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, by 2-way ANOVA (B) or unpaired Student’s t test (C–E and G).