SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells
Zhongqiu Wu, … , Zhengting Wang, Qiang Zou
Zhongqiu Wu, … , Zhengting Wang, Qiang Zou
Published February 10, 2022
Citation Information: J Clin Invest. 2022;132(7):e155224. https://doi.org/10.1172/JCI155224.
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Research Article Immunology Metabolism

SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells

Abstract

The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell–derived ROS triggered cytosolic SENP7–mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell–intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress–sensing machinery in tumor-infiltrating CD8+ T cells.

Authors

Zhongqiu Wu, Haiyan Huang, Qiaoqiao Han, Zhilin Hu, Xiao-Lu Teng, Rui Ding, Youqiong Ye, Xiaoyan Yu, Ren Zhao, Zhengting Wang, Qiang Zou

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Figure 1

ROS trigger cytosolic translocation of SENP7 in tumor-infiltrating CD8+ T cells.

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ROS trigger cytosolic translocation of SENP7 in tumor-infiltrating CD8+ ...
(A and B) Immunoblot analysis of the indicated proteins (A) and quantification of SENP7 expression (B, n = 6) in CD4+ and CD8+ T cells from CRC tissues. (C) Immunoblot analysis of the indicated proteins in CD4+ and CD8+ T cells from WT mice stimulated with anti-CD3 and anti-CD28 antibodies (α-CD3/28). (D–F) Immunoblot analysis using whole-cell lysates (WL) and nuclear (NF) and cytoplasmic (CF) fractions of CD8+ T cells from WT mice stimulated with anti-CD3 and anti-CD28 antibodies (D), CD8+ T cells from WT mice treated with 0.2 mM H2O2 for 1 hour (E), and CD8+ T cells from WT mice stimulated with anti-CD3 and anti-CD28 antibodies plus 10 mM NAC for 1 hour (F). (G and H) Histogram shows the MFI of ROS (G) and quantification of the MFI of ROS (H, n = 7) in CD8+ T cells from the spleens (Spl) and tumors (TIL) of tumor-bearing mice (day 7 after injection of tumors with MC38 cells). (I and J) Immunoblot analysis using CD8+ T cells from the spleens and tumors of tumor-bearing mice (I) and tumor-infiltrating CD8+ T cells treated with 10 mM NAC for 1 hour (J). (K and L) Histogram shows the MFI of ROS (K) and quantification of the MFI of ROS (L, n = 4) in CD8+ T cells from patient-derived PBMCs and CRC tissues. (M and N) Immunoblot analysis of the indicated proteins in CD8+ T cells from patient-derived PBMCs and CRC tissues (M) and CD8+ T cells from CRC tissues treated with 10 mM NAC for 1 hour (N). Representative data are shown from 2 (A, M, and N) and 3 (C–F, I, and J) independent experiments. *P < 0.05 and **P < 0.01, by Student’s t test (B, H and L).