Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer
Abstract We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer
2024-11-01
|
| Series: | Cancer Immunology, Immunotherapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00262-024-03864-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571696909910016 |
|---|---|
| author | Jenny Ling-Yu Chen Chun-Kai Pan Li-Cheng Lin Yu-Sen Huang Tsung-Hsuan Huang Shu-Jyuan Yang Sung-Hsin Kuo Yu-Li Lin |
| author_facet | Jenny Ling-Yu Chen Chun-Kai Pan Li-Cheng Lin Yu-Sen Huang Tsung-Hsuan Huang Shu-Jyuan Yang Sung-Hsin Kuo Yu-Li Lin |
| author_sort | Jenny Ling-Yu Chen |
| collection | DOAJ |
| description | Abstract We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes. |
| format | Article |
| id | doaj-art-ff5c38a2eed44e4e95e1811b56462ab3 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-ff5c38a2eed44e4e95e1811b56462ab32025-02-02T12:26:55ZengSpringerCancer Immunology, Immunotherapy1432-08512024-11-0174111510.1007/s00262-024-03864-6Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancerJenny Ling-Yu Chen0Chun-Kai Pan1Li-Cheng Lin2Yu-Sen Huang3Tsung-Hsuan Huang4Shu-Jyuan Yang5Sung-Hsin Kuo6Yu-Li Lin7Department of Radiology, National Taiwan University College of MedicineDepartment of Medical Research, National Taiwan University HospitalDepartment of Medical Research, National Taiwan University HospitalDepartment of Radiology, National Taiwan University College of MedicineDepartment of Medical Research, National Taiwan University HospitalInstitute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan UniversityNational Taiwan University Cancer Center, National Taiwan University College of MedicineDepartment of Medical Research, National Taiwan University HospitalAbstract We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.https://doi.org/10.1007/s00262-024-03864-6ATR inhibitionAblative radiotherapyImmune checkpoint inhibitorLung cancerSTING pathwayTumor microenvironment |
| spellingShingle | Jenny Ling-Yu Chen Chun-Kai Pan Li-Cheng Lin Yu-Sen Huang Tsung-Hsuan Huang Shu-Jyuan Yang Sung-Hsin Kuo Yu-Li Lin Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer Cancer Immunology, Immunotherapy ATR inhibition Ablative radiotherapy Immune checkpoint inhibitor Lung cancer STING pathway Tumor microenvironment |
| title | Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer |
| title_full | Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer |
| title_fullStr | Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer |
| title_full_unstemmed | Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer |
| title_short | Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer |
| title_sort | combination of ataxia telangiectasia and rad3 related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer |
| topic | ATR inhibition Ablative radiotherapy Immune checkpoint inhibitor Lung cancer STING pathway Tumor microenvironment |
| url | https://doi.org/10.1007/s00262-024-03864-6 |
| work_keys_str_mv | AT jennylingyuchen combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT chunkaipan combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT lichenglin combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT yusenhuang combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT tsunghsuanhuang combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT shujyuanyang combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT sunghsinkuo combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer AT yulilin combinationofataxiatelangiectasiaandrad3relatedinhibitionwithablativeradiotherapyremodelsthetumormicroenvironmentandenhancesimmunotherapyresponseinlungcancer |