Intrinsic RIG-I restrains STAT5 activation to modulate antitumor activity of CD8+ T cells
Xinyi Jiang, Jian Lin, Chengfang Shangguan, Xiaoyao Wang, Bin Xiang, Juan Chen, Hezhou Guo, Wu Zhang, Jun Zhang, Yan Shi, Jiang Zhu, Hui Yang
Xinyi Jiang, Jian Lin, Chengfang Shangguan, Xiaoyao Wang, Bin Xiang, Juan Chen, Hezhou Guo, Wu Zhang, Jun Zhang, Yan Shi, Jiang Zhu, Hui Yang
View: Text | PDF
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

×

Figure 8

Frequency of RIG-I+ tumor-infiltrating CD8+ T cells associates with the poor prognosis for patients with colon cancer.

Options: View larger image (or click on image) Download as PowerPoint
Frequency of RIG-I+ tumor-infiltrating CD8+ T cells associates with the ...
(A–F) Publicly available scRNA-Seq data from 12 individuals with CRC were analyzed, focusing on tumor-infiltrating CD8+ T cells and CD8+ T cells from adjacent nonmalignant tissues. Data are from GSE108989. Box plot showing the expression of RIG-I in CD8+ T cells from adjacent nonmalignant tissues (Normal) or tumor tissues (Tumor) (A). Violin plot showing the expression of RIG-I in indicated subsets of CD8+ T cells (B). GSEA plots showing enriched T cell activation (C), IFN-γ response (D), apoptosis by serum deprivation (E) and STAT5a target gene signatures (F) in tumor-infiltrating CD8+ T cells with high versus low RIG-I expression. (G and H) Slides of tumor tissue from colorectal carcinoma patients were costained by RIG-I antibody (green) and CD8 antibody (red). DAPI was used to visualize the nuclei (blue). Representative images (G) and the proportion of CD8+RIG-I+ cells of CD8+ cells from stage I–III or stage IV patients were shown (H). (I) The percentages of CD8+ T cells in nucleated cells for RIG-I+ CD8+ low group or RIG-I+ CD8+ high group are shown. (J) Kaplan-Meier plot depicting OS of patients from RIG-I+CD8+–low group or RIG-I+CD8+–high group are shown. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001, by unpaired Student’s t test (A, B, H, and I) or log-rank test (J).