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
View: Text | PDF
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

×

Figure 7

Targeting TARBP2 sensitizes RCC to adoptive NK cell therapy and ICB therapy.

Options: View larger image (or click on image) Download as PowerPoint
Targeting TARBP2 sensitizes RCC to adoptive NK cell therapy and ICB ther...
(A) Representative multiplex IHC staining of pan-cytokeratin (PanCK), TARBP2, B7-H3, CD3, CD56, and DAPI in RCC samples from ICB responders and nonresponders. Scale bars: 50 μm and 50 μm (insets). (B) Quantification of nuclear TARBP2+, B7-H3+, CD3+, and CD3–CD56+ cells in RCC samples from ICB responders and nonresponders (n = 5 patients/group). (C) Illustration of the RCC PDX model in immunodeficient NCG mice treated with adoptive NK cell transfer and siRNA at the indicated time points. (D–F) Tumor images (D), weights (E), and growth curves (F) in the indicated PDX groups (n = 5 mice/group). (G) Representative PDX tumor sections from NCG mice treated with siRNA and adoptive NK-92MI cell transfer stained with H&E, TARBP2, B7-H3, and Cleaved Caspase-3. Scale bar: 50 μm. (H) Proportion of CD107a+ cells among CD3–CD56+ NK cells in PDX tumors (n = 5 mice/group). (I) Schematic of Renca-derived orthotopic tumors in BALB/c mice treated with adoptive NK cell transfer, anti–PD-1 antibody, and anti–B7-H3 antibody at the indicated time points. (J and K) Quantification of bioluminescence intensity (J) and representative bioluminescence images (K) of orthotopic tumors from the indicated groups (n = 5 mice/group). (L) Proportions of CD3–CD49b+ NK cells among CD45+ cells, CD107a+ cells among NK cells, and the ratio of PKH26+ transferred NK cells to PKH26− endogenous NK cells in orthotopic tumors from the indicated groups (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 H, by 1-way ANOVA followed by Tukey’s multiple-comparison test in E and L, and by 2-way ANOVA followed by Bonferroni’s multiple-comparison test in F and J. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.