Radiotherapy-resistant prostate cancer cells escape immune checkpoint blockade through the senescence-related ataxia telangiectasia and Rad3-related protein.

Autor: Shao C; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China., Zhang Y; School of Disaster and Emergency Medicine, Tianjin University, Tianjin, P. R. China.; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA., Li H; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China., Chen J; Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, P. R. China., Huang T; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China., Li J; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China., Wen S; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, P. R. China., Wang S; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China., Fan S; Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China., Zhao Y; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P. R. China.
Jazyk: angličtina
Zdroj: Cancer communications (London, England) [Cancer Commun (Lond)] 2024 Dec 19. Date of Electronic Publication: 2024 Dec 19.
DOI: 10.1002/cac2.12636
Abstrakt: Background: The majority of patients with prostate cancer (PCa) exhibit intrinsic resistance to immune checkpoint blockade (ICB) following radiotherapy (RT). This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors. Here, we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB.
Methods: Single-cell RNA-sequencing (scRNA-seq) was used to profile senescent cancer cell clusters induced by RT in LNCaP cells. The expression and phosphorylation levels of ataxia telangiectasia and Rad3-related protein (ATR) were assessed by immunohistochemistry in clinical samples from patients with or without RT. Co-immunoprecipitation, mutagenesis, and Western blotting were used to measure the interactions between proteins. Xenograft experiments were performed to assess the tumor immune response in the mice.
Results: We identified a subset of PCa cells that exhibited resistance to RT, characterized by a reduced antigen presentation capability, which enhanced their ability to evade immune detection and resist cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. scRNA-seq revealed that the senescent state was a transient phase of PCa cells post-RT, particularly in CTLA-4 blockade treatment-resistant cells. This state was marked by increased cytosolic ATR level. Cytosolic ATR phosphorylated CD86 in its cytosolic domain and enhanced the interaction between CD86 and its E3 ligase MARCH1 through electrostatic attraction. Depletion or inhibition of Atr increased the sensitivity to immune attack and improved responses to anti-Ctla-4 antibody treatment in a mouse model.
Conclusions: Our findings indicate that the activation of cytosolic ATR, which is associated with cellular senescence, impedes the effectiveness of combined RT and ICB treatments. This discovery may provide valuable insights for improving the efficacy of combined RT and ICB therapies in PCa.
(© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.)
Databáze: MEDLINE
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