UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer
Jun Xiao, … , Cong-Yi Wang, Zhi-Hua Wang
Jun Xiao, … , Cong-Yi Wang, Zhi-Hua Wang
Published January 10, 2023
Citation Information: J Clin Invest. 2023;133(4):e158352. https://doi.org/10.1172/JCI158352.
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Research Article Immunology Oncology

UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer

Abstract

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage–CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Authors

Jun Xiao, Fei Sun, Ya-Nan Wang, Bo Liu, Peng Zhou, Fa-Xi Wang, Hai-Feng Zhou, Yue Ge, Tian-Tian Yue, Jia-Hui Luo, Chun-Liang Yang, Shan-Jie Rong, Ze-Zhong Xiong, Sheng Ma, Qi Zhang, Yang Xun, Chun-Guang Yang, Yang Luan, Shao-Gang Wang, Cong-Yi Wang, Zhi-Hua Wang

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Figure 7

Inhibition of UBC9 represses prostate tumor growth synergistically with anti–PD-1 therapy.

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Inhibition of UBC9 represses prostate tumor growth synergistically with ...
(A–C) Tumor growth curve (A) and tumor mass (B and C) following CD8+ T cell depletion at day 14 in WT and Ubc9–/– mice bearing PCa tumors (n = 7 per group). (D) Experimental design of combined therapy using 2-D08 and anti–PD-1 antibody in prostate tumors. (E–G) Prostate tumor growth curve (E) and tumor mass (F and G) at day 14 in PCa-bearing mice treated with DMSO, 2-D08, anti–PD-1 antibody, or 2-D08 plus anti–PD-1 antibody (n = 7 per group). (H) Percentage of CD4+ and CD8+ T cells among CD45+ immune cells in the 4 groups (n = 4 per group). (I) Proportions of IFN-γ+ CD8+ T cells in the 4 groups (n = 4 per group). A and E were determined by log-rank test. Data in B, F, and I represent mean ± SEM and were analyzed by Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (J) Schematic model depicting the antitumor effect of UBC9 inhibition in TAMs. Inhibition of STAT4 SUMOylation leads to TAM activation and enhanced antigen cross-presentation to CD8+ T cells, which are responsible for the cytotoxicity on PCa cells. Alternatively, the UBC9 inhibitor 2-D08 exerts a direct tumor-killing effect, leading to the release of tumor-associated antigens.