EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1
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...
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202206792 |
| _version_ | 1797846484818853888 |
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| author | Yihui Pan Guannan Shu Liangmin Fu Kangbo Huang Xinwei Zhou Chengpeng Gui Huashan Liu Xiaohan Jin Minyu Chen Pengju Li Junjie Cen Zihao Feng Jun Lu Zhenhua Chen Jiaying Li Quanhui Xu Yinghan Wang Hui Liang Zhu Wang Qiong Deng Wei Chen Junhang Luo Jiefeng Yang Jiaxing Zhang Jinhuan Wei |
| author_facet | Yihui Pan Guannan Shu Liangmin Fu Kangbo Huang Xinwei Zhou Chengpeng Gui Huashan Liu Xiaohan Jin Minyu Chen Pengju Li Junjie Cen Zihao Feng Jun Lu Zhenhua Chen Jiaying Li Quanhui Xu Yinghan Wang Hui Liang Zhu Wang Qiong Deng Wei Chen Junhang Luo Jiefeng Yang Jiaxing Zhang Jinhuan Wei |
| author_sort | Yihui Pan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:56:46Z |
| format | Article |
| id | doaj.art-61779df20f7547ad966d1eb6dbf1aeba |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-09T17:56:46Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-61779df20f7547ad966d1eb6dbf1aeba2023-04-14T19:54:20ZengWileyAdvanced Science2198-38442023-04-011011n/an/a10.1002/advs.202206792EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1Yihui Pan0Guannan Shu1Liangmin Fu2Kangbo Huang3Xinwei Zhou4Chengpeng Gui5Huashan Liu6Xiaohan Jin7Minyu Chen8Pengju Li9Junjie Cen10Zihao Feng11Jun Lu12Zhenhua Chen13Jiaying Li14Quanhui Xu15Yinghan Wang16Hui Liang17Zhu Wang18Qiong Deng19Wei Chen20Junhang Luo21Jiefeng Yang22Jiaxing Zhang23Jinhuan Wei24Department of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology Sun Yat‐sen University Cancer Center Guangzhou 510060 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Colorectal Surgery and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology Affiliated Longhua People's Hospital Southern Medical University Shenzhen 518109 ChinaDepartment of Urology Affiliated Longhua People's Hospital Southern Medical University Shenzhen 518109 ChinaDepartment of Urology Affiliated Longhua People's Hospital Southern Medical University Shenzhen 518109 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Oncology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Urology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaAbstract 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.https://doi.org/10.1002/advs.202206792EHBP1L1IFN‐γ/JAK1/STAT1/PD‐L1 signalingimmune evasionrenal cell carcinoma |
| spellingShingle | Yihui Pan Guannan Shu Liangmin Fu Kangbo Huang Xinwei Zhou Chengpeng Gui Huashan Liu Xiaohan Jin Minyu Chen Pengju Li Junjie Cen Zihao Feng Jun Lu Zhenhua Chen Jiaying Li Quanhui Xu Yinghan Wang Hui Liang Zhu Wang Qiong Deng Wei Chen Junhang Luo Jiefeng Yang Jiaxing Zhang Jinhuan Wei EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1 Advanced Science EHBP1L1 IFN‐γ/JAK1/STAT1/PD‐L1 signaling immune evasion renal cell carcinoma |
| title | EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1 |
| title_full | EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1 |
| title_fullStr | EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1 |
| title_full_unstemmed | EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1 |
| title_short | EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1 |
| title_sort | ehbp1l1 drives immune evasion in renal cell carcinoma through binding and stabilizing jak1 |
| topic | EHBP1L1 IFN‐γ/JAK1/STAT1/PD‐L1 signaling immune evasion renal cell carcinoma |
| url | https://doi.org/10.1002/advs.202206792 |
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