LC3-dependent intercellular transfer of phosphorylated STAT1/2 elicits CXCL9+ macrophages and enhances radiation-induced antitumor immunity
Jun-Yan Li, Ying-Qing Li, Jia-Hao Dai, Sha Gong, Qing-Mei He, Jie-Wen Bai, Sai-Wei Huang, Ying-Qi Lu, Yu-Fei Duan, Sen-Yu Feng, Xi-Rong Tan, Xiao-Yu Liang, Jun Ma, Rui Guo, Na Liu
Jun-Yan Li, Ying-Qing Li, Jia-Hao Dai, Sha Gong, Qing-Mei He, Jie-Wen Bai, Sai-Wei Huang, Ying-Qi Lu, Yu-Fei Duan, Sen-Yu Feng, Xi-Rong Tan, Xiao-Yu Liang, Jun Ma, Rui Guo, Na Liu
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Research Article Cell biology Immunology Oncology

LC3-dependent intercellular transfer of phosphorylated STAT1/2 elicits CXCL9+ macrophages and enhances radiation-induced antitumor immunity

Abstract

The efficacy of anticancer treatments, including radiotherapy, depends on the activation of type I IFN signaling. However, its regulatory networks and mechanisms remain to be elucidated. Here, we report that tumor cell–intrinsic type I IFN signaling can be transferred to macrophages via secretory autophagy, inducing CXCL9hi macrophages and enhancing CD8+ T cell–mediated antitumor immunity. Mechanistically, K63-linked ubiquitination at the K167 site of phosphorylated STAT2 (p-STAT2) facilitates its binding to LC3B, promoting the loading of p-STAT1 and p-STAT2 into extracellular vesicles and intercellular transference from tumor cells to macrophages, which, however, is suppressed by USP5-mediated STAT2 deubiquitination. Genetic depletion or pharmacological inhibition of USP5 promotes autophagy-dependent unconventional protein secretion of p-STAT1 and p-STAT2, leading to the induction of CXCL9+ macrophages. This process promotes the expression of T cell chemokines and upregulates the antigen presentation machinery, thereby enhancing radiation-induced CD8+ T cell antitumor immunity and radiotherapy efficacy. Our findings reveal a critical role of USP5 in type I IFN–induced antitumor immunity, providing potential targets for improving the efficacy of radiotherapy.

Authors

Jun-Yan Li, Ying-Qing Li, Jia-Hao Dai, Sha Gong, Qing-Mei He, Jie-Wen Bai, Sai-Wei Huang, Ying-Qi Lu, Yu-Fei Duan, Sen-Yu Feng, Xi-Rong Tan, Xiao-Yu Liang, Jun Ma, Rui Guo, Na Liu

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Figure 3

USP5 depletion promotes CXCL9+ macrophages and CD8+ T cell antitumor immunity in a tumor-intrinsic IFN-I signaling–dependent manner.

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USP5 depletion promotes CXCL9+ macrophages and CD8+ T cell antitumor imm...
(A–D) Every 3 days, 100 μL PBS or clodronate liposome was intratumorally injected, starting 3 days before CT26 or B16 tumor inoculation. The CD3+CD8+ T cells and their GZMB+ T cell subset in CT26 tumors were measured (B, n = 5 per group). The growth rates of CT26 tumors (C) and B16 tumors (D) are reported (n = 6 per group). (E and F) Anti-Ifnar1 antibody was intraperitoneally administered (days 7, 10, and 13) to C57BL/6 mice bearing control or Usp5-deficient B16 tumors. The tumor growth (E) and tumor weights (F) are reported (n = 6 per group). (G–J). Ifnar1-intact or -deficient B16 tumor cells were inoculated into C57BL/6 mice, and the tumors were subjected to radiation. The tumor growth (G, n = 6 per group), CXCL9+CD11b+ macrophages (H, n = 6 per group), proportions of total macrophages and iNOS+ subsets (I, n = 5 per group), and GZMB+CD8+ or TNF-α+CD8+ T cells (J, n = 5 per group) are reported. The data are presented as mean ± SD. Comparisons were performed using 2-way ANOVA with Bonferroni’s test for multiple comparisons (B–J). **P < 0.01, ***P < 0.001, ****P < 0.0001.