TARBP2 facilitates renal cell carcinoma immune escape by suppressing 53BP1 phase separation to upregulate B7-H3
Minyu Chen, Mingjie Lin, Jiangquan Zhu, Kezhi Liu, Guannan Shu, Zhuting Tong, Mi Zhou, Liangmin Fu, Taowei Yang, Yihui Pan, Xinwei Zhou, Jinchen Luo, Wuyuan Liao, Qihao Li, Lican Liao, Hansen Lin, Kangbo Huang, Lizhen Zhang, Wei Chen, Junhang Luo, Jiaxing Zhang
Minyu Chen, Mingjie Lin, Jiangquan Zhu, Kezhi Liu, Guannan Shu, Zhuting Tong, Mi Zhou, Liangmin Fu, Taowei Yang, Yihui Pan, Xinwei Zhou, Jinchen Luo, Wuyuan Liao, Qihao Li, Lican Liao, Hansen Lin, Kangbo Huang, Lizhen Zhang, Wei Chen, Junhang Luo, Jiaxing Zhang
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Research Article Immunology Oncology

TARBP2 facilitates renal cell carcinoma immune escape by suppressing 53BP1 phase separation to upregulate B7-H3

Abstract

Renal cell carcinoma (RCC) harbors an immunosuppressive tumor microenvironment that facilitates immune evasion and resistance to immune checkpoint blockade (ICB). However, the factors driving immune escape in RCC remain incompletely understood. In this study, transactivation response RNA-binding protein 2 (TARBP2) was identified as a critical regulator of the immune checkpoint molecule B7-H3. Elevated TARBP2 expression was associated with poor prognosis and ICB resistance in patients with RCC. Functionally, TARBP2 in RCC cells suppressed the intratumoral accumulation and cytotoxicity of T cells, particularly NK cells, thereby promoting immune escape. Mechanistically, nuclear TARBP2 interacted with p53-binding protein 1 (53BP1), inhibiting 53BP1 phase separation and subsequent p53 activation, thereby augmenting B7-H3 transcription. Furthermore, TARBP2 inhibition significantly enhanced ICB efficacy when combined with adoptive NK cell therapy. Collectively, these findings establish TARBP2 as a key mediator of immune evasion in RCC and a promising therapeutic target for overcoming ICB resistance.

Authors

Minyu Chen, Mingjie Lin, Jiangquan Zhu, Kezhi Liu, Guannan Shu, Zhuting Tong, Mi Zhou, Liangmin Fu, Taowei Yang, Yihui Pan, Xinwei Zhou, Jinchen Luo, Wuyuan Liao, Qihao Li, Lican Liao, Hansen Lin, Kangbo Huang, Lizhen Zhang, Wei Chen, Junhang Luo, Jiaxing Zhang

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Figure 3

TARBP2 suppresses NK cell–mediated antitumor immunity in RCC.

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TARBP2 suppresses NK cell–mediated antitumor immunity in RCC. (A) Experi...
(A) Experimental design of Renca-derived tumors with or without Tarbp2 knockdown in BALB/c mice treated with isotype control, CD4+ T cell–depleting antibody (αCD4), CD8+ T cell–depleting antibody (αCD8), or NK cell–depleting antibody (αNK). (B–D) Tumor images (B), weights (C), and growth curves (D) (n = 5 mice per group). (E) Workflow for isolating CD3–NKp46+ cells from Renca-derived tumors for scRNA-seq. (F) Proportions of clusters in Tarbp2-knockdown versus control tumors. (G) Dot plots of key marker genes defining clusters from FACS-sorted CD3–NKp46+ cells, including NK/NKT cell markers, surface receptors, transcription factors (TFs), integrins, cytotoxic molecules, cytokines, inhibitory molecules, and proliferation markers. (H) Expression of Cd69, Ifng, Ccl4, and Tigit. (I) Gene Ontology (GO) and KEGG enrichment analyses in clusters 2 and 3. (J) NK activation and TGF-β signaling signature scores across clusters. (K) Comparison and correlation of the NK activation and TGF-β signaling signature scores in clusters 2 and 3. (L) Heatmap showing transcription factor regulon activity associated with NK cell activation and proliferation over pseudotime. (M) Apoptotic rates (%, annexin V+) of primary RCC cells after incubation with NK-92MI or peripheral NK cells at different E/T ratios for 8 h (n = 3 independent experiments). (N) Proportions of CD107a+, TNF-α+, and IFN-γ+ NK cells after incubation with primary RCC cells (E/T = 1:1, 8 h; n = 3 independent experiments). All data are presented as mean ± SD. Statistics were analyzed by 1-way ANOVA followed by Tukey’s multiple-comparison test in C, by 2-way ANOVA followed by Bonferroni’s multiple-comparison test in D, by χ2 test in F, by Mann-Whitney test for violin plots and Spearman’s correlation for scatterplot in K, and by 1-way ANOVA followed by Dunnett’s multiple-comparison test in M and N. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.