Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein
Abstract 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 is...
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Wiley
2025-03-01
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| Series: | Cancer Communications |
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| Online Access: | https://doi.org/10.1002/cac2.12636 |
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| author | Chenyi Shao Yingyi Zhang Hang Li Jiajia Chen Ting Huang Jiaze Li Simeng Wen Sen Wang Saijun Fan Yu Zhao |
| author_facet | Chenyi Shao Yingyi Zhang Hang Li Jiajia Chen Ting Huang Jiaze Li Simeng Wen Sen Wang Saijun Fan Yu Zhao |
| author_sort | Chenyi Shao |
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| description | Abstract 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. |
| format | Article |
| id | doaj-art-ad58dae963e8486c8e6d9d99edc91c0e |
| institution | OA Journals |
| issn | 2523-3548 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj-art-ad58dae963e8486c8e6d9d99edc91c0e2025-08-20T02:10:46ZengWileyCancer Communications2523-35482025-03-0145321824410.1002/cac2.12636Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related proteinChenyi Shao0Yingyi Zhang1Hang Li2Jiajia Chen3Ting Huang4Jiaze Li5Simeng Wen6Sen Wang7Saijun Fan8Yu Zhao9Tianjin 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. ChinaSchool of Disaster and Emergency Medicine Tianjin University Tianjin P. R. ChinaTianjin 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. ChinaDepartment of Oncology Shengjing Hospital of China Medical University Shenyang Liaoning P. R. ChinaTianjin 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. ChinaTianjin 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. ChinaDepartment of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin P. R. ChinaTianjin 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. ChinaInstitute of Radiation Medicine Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin P. R. ChinaTianjin 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. ChinaAbstract 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.https://doi.org/10.1002/cac2.12636ATRCD86immune checkpointsenescence |
| spellingShingle | Chenyi Shao Yingyi Zhang Hang Li Jiajia Chen Ting Huang Jiaze Li Simeng Wen Sen Wang Saijun Fan Yu Zhao Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein Cancer Communications ATR CD86 immune checkpoint senescence |
| title | Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein |
| title_full | Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein |
| title_fullStr | Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein |
| title_full_unstemmed | Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein |
| title_short | Radiotherapy‐resistant prostate cancer cells escape immune checkpoint blockade through the senescence‐related ataxia telangiectasia and Rad3‐related protein |
| title_sort | radiotherapy resistant prostate cancer cells escape immune checkpoint blockade through the senescence related ataxia telangiectasia and rad3 related protein |
| topic | ATR CD86 immune checkpoint senescence |
| url | https://doi.org/10.1002/cac2.12636 |
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