1. Academic Validation
  2. TMEM160 promotes tumor immune evasion and radiotherapy resistance via PD-L1 binding in colorectal cancer

TMEM160 promotes tumor immune evasion and radiotherapy resistance via PD-L1 binding in colorectal cancer

  • Cell Commun Signal. 2024 Mar 7;22(1):168. doi: 10.1186/s12964-024-01541-w.
Xiaofeng Dai # 1 2 Zhipeng Wu # 1 2 Ruiwen Ruan 1 2 Jingyi Chen 1 2 Chunye Huang 1 2 Wan Lei 1 Yangyang Yao 1 Li Li 1 Xiaomei Tang 3 Jianping Xiong 4 Miao Feng 5 Jun Deng 6 7
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China.
  • 2 Jiangxi Key Laboratory for Individual Cancer Therapy, 17 Yongwai Street, Nanchang, Jiangxi Province, 330006, China.
  • 3 Department of Oncology, Jiangxi Provincial Chest Hospital, Nanchang, Jiangxi Province, 330006, China. tangxiaomei2020@126.com.
  • 4 Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China. Jpxiong0630@outlook.com.
  • 5 Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China. farrahm@163.com.
  • 6 Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China. dengjun19871106@ncu.edu.cn.
  • 7 Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China. dengjun19871106@ncu.edu.cn.
  • # Contributed equally.
Abstract

Background: The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of Cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal Cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear.

Methods: Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC).

Results: In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor growth derived from lentiviral vector shTMEM160 cells was lower compared with that derived from shNC control cells. Furthermore, the downregulation of TMEM160 significantly restricted tumor growth in immune-competent BALB/c mice. In clinical samples from patients with CRC, we observed a strong positive correlation between TMEM160 expression and PD-L1 expression, as well as a negative correlation with CD8a expression. Importantly, patients with high TMEM160 expression exhibited a worse prognosis compared with those with low or no TMEM160 expression.

Conclusions: Our study reveals that TMEM160 inhibits the ubiquitination-dependent degradation of PD-L1 that is mediated by SPOP, thereby stabilizing PD-L1 expression to foster the malignant progress, radioresistance, and immune evasion of CRC cells. These findings suggest that TMEM160 holds potential as a target for the treatment of patients with CRC.

Keywords

Colorectal cancer; PD-L1; SPOP; TMEM160.

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