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 4

TARBP2/p53/B7-H3 axis regulates NK cell antitumor function in RCC.

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TARBP2/p53/B7-H3 axis regulates NK cell antitumor function in RCC. (A) D...
(A) Differentially expressed genes between tumor cells isolated from shTarbp2 and control Renca-derived tumors (n = 5 mice/group). (B) B7-H3 expression in RCC ICB pretreatment FFPE samples from responders and nonresponders (n = 3 patients/group). (C) Cell surface B7-H3 on isolated tumor cells (n = 5 mice/group). (D and E) Spearman’s correlations between TARBP2 and 38 common immune checkpoint genes across 33 TCGA cancer types (D) or RCC-related datasets (E). POS, positive; NEG, negative. (F) Representative IHC images of RCC tissues stained for TARBP2 and B7-H3. Scale bar: 100 μm (left). Spearman’s correlation between TARBP2 and B7-H3 H-scores (right; n = 40 samples). (G) GSEA of the p53 signaling pathway in isolated tumor cells (n = 5 mice/group). (H) Cell surface B7-H3 levels in TARBP2-knockdown and control 769-P cells (n = 3 independent experiments). (I) Total B7-H3, p53, and p21 protein levels in TARBP2-knockdown and control 769-P cells. GAPDH served as loading control. (J and K) Cell surface (J) and total (K) B7-H3 levels in TP53-knockdown 769-P cells with TARBP2 knockdown or control. (L) B7-H3 promoter–driven reporter activity in 769-P cells under control, TARBP2-knockdown, or TARBP2/TP53–co-knockdown conditions (n = 4 independent experiments). Relative luciferase activities were normalized to vector control samples. (M and N) Tumor weights (M) and growth curves (N) (n = 5 mice/group). (O) Proportions of CD3–CD49b+ NK cells within CD45+ cells and frequencies of CD107a+ cells among NK cells in indicated tumors (n = 5 mice/group). All data are presented as mean ± SD. Statistics were analyzed by unpaired 2-tailed Student’s t test in B and C, by 1-way ANOVA followed by Dunnett’s multiple-comparison test in H, by 1-way ANOVA followed by Tukey’s multiple-comparison test in J and L, and by 2-way ANOVA followed by Tukey’s multiple-comparison test in N and O. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.