2. Academic Validation
  3. EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

  • Adv Sci (Weinh). 2023 Feb 12;e2206792. doi: 10.1002/advs.202206792.
Yihui Pan 1 2,  Guannan Shu 1,  Liangmin Fu 1,  Kangbo Huang 3 4,  Xinwei Zhou 1,  Chengpeng Gui 1,  Huashan Liu 5,  Xiaohan Jin 1,  Minyu Chen 1,  Pengju Li 1,  Junjie Cen 1,  Zihao Feng 1,  Jun Lu 1,  Zhenhua Chen 1,  Jiaying Li 1,  Quanhui Xu 1,  Yinghan Wang 1,  Hui Liang 6,  Zhu Wang 6,  Qiong Deng 6,  Wei Chen 1,  Junhang Luo 1,  Jiefeng Yang 1,  Jiaxing Zhang 7,  Jinhuan Wei 1
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 2 Department of Urology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, 213003, China.
  • 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
  • 4 Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 5 Department of Colorectal Surgery and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
  • 6 Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, 518109, China.
  • 7 Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
PMID: 36775874 DOI: 10.1002/advs.202206792
Abstract

High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN-γ-induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain-binding protein 1-like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN-γ/JAK1/STAT1/PD-L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell-mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD-L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient-derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

Keywords

EHBP1L1; IFN-γ/JAK1/STAT1/PD-L1 signaling; immune evasion; renal cell carcinoma.

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