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 1

TARBP2 correlates with poor prognosis and ICB resistance in RCC and is predominantly expressed in malignant RCC cells.

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TARBP2 correlates with poor prognosis and ICB resistance in RCC and is p...
(A) Venn diagram depicting overlapped genes in data mining. DEGs, differentially expressed genes. (B) Scatterplot illustrating differentially expressed genes in RCC ICB pretreatment FFPE samples between ICB responders and nonresponders (n = 3 samples from different patients per group). (C) TARBP2 (top) and GINS3 (bottom) expression in low-stage (I–II, n = 323) and high-stage (III–IV, n = 206) RCC from the TCGA-KIRC cohort. Boxes represent the IQR, with the center line indicating the median. Whiskers extend to values within 1.5-fold of the IQR, and points beyond the whiskers are shown as outliers. (D) Waterfall plot of TARBP2 expression (z score) across progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR) samples in the CheckMate cohort (n = 172 samples). (E and F) OS of RCC patients with low or high TARBP2 expression in the E-MTAB-1980 cohort (E) and Riaz2017_PD1_Melanoma cohort (F). (G) Top: Representative IHC images of RCC tissues with low or high TARBP2 H-score in the SYSU cohort. Scale bar: 100 μm. Bottom: OS of RCC patients with low (n = 60) or high (n = 60) TARBP2 H-score in the SYSU cohort. (H) Uniform manifold approximation and projection (UMAP) of 192,626 cells classified into 12 cell populations. (I) UMAP of reclustered epithelial and RCC cells. (J) Differentiation trajectories from epithelial cells to E-RCC cells and subsequently to RCC cells. (K) Dynamic TARBP2 expression over pseudotime. (L) TARBP2 expression levels and proportions of TARBP2+ cells across cell types in all samples regardless of ICB treatment status. (M) Immune response activation scores of E-RCC and RCC cells. Statistics were analyzed by Mann-Whitney test in C and M and by log-rank test in E and F. ****P < 0.0001; **P < 0.01; *P < 0.05.