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 2

TARBP2 impairs immune-mediated tumor suppression in RCC.

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TARBP2 impairs immune-mediated tumor suppression in RCC. (A) Schematic o...
(A) Schematic of subcutaneous implantation of control or Tarbp2-knockdown Renca cells into NCG mice. (B–D) Tumor images (B), weights (C), and growth curves (D) of the indicated groups in NCG mice (n = 6 mice per group). (E) Schematic of subcutaneous implantation of control or Tarbp2-knockdown Renca cells into BALB/c mice. (F–H) Tumor images (F), weights (G), and growth curves (H) of the indicated groups in BALB/c mice (n = 5 mice per group). (I) Proportions of CD8+ T cells, CD4+ T cells, and CD3–CD49b+ NK cells in CD45+ cells from the indicated Renca-derived tumors in BALB/c mice (n = 5 mice per group). (J) Proportions of granzyme B+ (GZMB) cells in CD8+ T cells, CD4+ T cells, and NK cells from the indicated Renca-derived tumors in BALB/c mice (n = 5 mice per group). (K and L) Cell proliferation and apoptosis in tumor sections from BALB/c mice, as assessed by Ki67 (K) and TUNEL (L) staining, respectively (n = 5 mice per group). Scale bars: 50 μm. (M and N) The potential intercellular communication based on the calculation of interactive ligands-receptors between RCC/E-RCC cells and other cells in ICB-untreated (M) and ICB-treated (N) patient samples. Lines link cell types expressing the cognate receptors or ligands. Line thickness represents the inferred communication strength. (O) Dot plot showing immune checkpoint–related ligand-receptor pairs between RCC/E-RCC cells and T/NK cells. All data are presented as mean ± SD. Statistics were analyzed by 1-way ANOVA followed by Dunnett’s multiple-comparison test for comparisons with the control group in C, G, and I–L and by 2-way ANOVA followed by Bonferroni’s multiple-comparison test in D and H. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.