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 5

TARBP2 disrupts 53BP1-p53 complex formation and chromatin accumulation.

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TARBP2 disrupts 53BP1-p53 complex formation and chromatin accumulation. ...
(A) Top: Representative IHC staining of TARBP2. Scale bar: 50 μm. Bottom: H-score of nuclear TARBP2 in low- and high-grade RCC tissues from the SYSU cohort (n = 120 samples). Boxes represent the IQR, center lines indicate the median, whiskers extend to 1.5-fold of the IQR, and dots indicate outliers. (B) Workflow of nucleocytoplasmic separation, co-IP, and mass spectrometry identifying nuclear TARBP2–53BP1 interaction. (C–E) Co-IP assays showing interaction between endogenous TARBP2 and 53BP1 in 769-P cells (C and D) and between overexpressed TARBP2-FLAG and 53BP1-HA in Caki-1 cells (E). EV, empty vector. (F) 3D structured illumination microscopy rendering of 769-P cells stained to indicate TARBP2 (green) and 53BP1 (red) colocalization (yellow). Scale bars: 5 μm and 1 μm (insets). The x–y plane represents lateral cross-sectional views parallel to the substrate surface, and the z axis indicates axial dimension perpendicular to the substrate surface. (G and H) Total 53BP1 levels in 769-P (G) or Caki-1 (H) cells. GAPDH served as loading control. (I and J) Representative confocal images (left) and quantification of 53BP1 foci (right) in 769-P (I) or Caki-1 (J) cells (n > 120 nuclei/group). Dashed lines outline nuclei. Scale bars: 5 μm. (K and L) 53BP1 and p53 levels in chromatin fractions of 769-P (K) or Caki-1 (L) cells. Histone H3 and H4 served as chromatin loading controls. (M) Representative images (left) and quantification (right) of endogenous TARBP2-53BP1 and 53BP1-p53 interactions in 769-P cells (n > 100 nuclei/group). DAPI (blue) marks nuclei, and red dots indicate positive signals. Scale bar: 5 μm. (N) Sequential co-IP assays demonstrating distinct endogenous TARBP2-53BP1 and 53BP1-p53 complexes. Solid lines indicate medians in I (right), J (right), and M (right). Statistics were analyzed by unpaired 2-tailed Student’s t test in A, by Kruskal-Wallis test followed by Dunn’s multiple-comparison test in I and M, and by Mann-Whitney test in J. ****P < 0.0001; ***P < 0.001; *P < 0.05.