Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation
Background Patients with microsatellite stable (MSS) colorectal cancer (CRC) often display resistance to immunotherapy. Epidermal growth factor receptor (EGFR)-targeted therapies have shown potential in enhancing immunotherapy, yet clinical benefits remain unfulfilled, which may relate to inadequate...
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BMJ Publishing Group
2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e010126.full |
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| author | Jing Wu Yang Zhao Min Shi Yong Li Yu Jiang Fei Sun Jianjun Peng Jiao Wang Qiong Huang Na Huang Yawen Wang Yulu Shi Xiaoxiang Rong Wangjun Liao Chunlin Wang Fangzhen Yao Chunting Zeng Bishan Liang Shaowei Li Qijing Wu Zhiqi Yao Chunhui Gu Yujing Tan |
| author_facet | Jing Wu Yang Zhao Min Shi Yong Li Yu Jiang Fei Sun Jianjun Peng Jiao Wang Qiong Huang Na Huang Yawen Wang Yulu Shi Xiaoxiang Rong Wangjun Liao Chunlin Wang Fangzhen Yao Chunting Zeng Bishan Liang Shaowei Li Qijing Wu Zhiqi Yao Chunhui Gu Yujing Tan |
| author_sort | Jing Wu |
| collection | DOAJ |
| description | Background Patients with microsatellite stable (MSS) colorectal cancer (CRC) often display resistance to immunotherapy. Epidermal growth factor receptor (EGFR)-targeted therapies have shown potential in enhancing immunotherapy, yet clinical benefits remain unfulfilled, which may relate to inadequate patient stratification.Methods Circulating tumor cells and tumor tissues were collected from multicenter cohorts of patients with CRC receiving cetuximab to analyze EGFR variant type III (EGFRvIII) expression and immune infiltration. Syngeneic mouse models of EGFRvIII CRC were used to investigate the combined efficacy of adenosine inhibition and antiprogrammed cell death protein 1 (anti-PD-1).Results EGFRvIII mutations are found in about 10% of MSS CRC and are associated with poor response to cetuximab therapy. EGFRvIII-mutated patients with CRC exhibit an adenosine-mediated immunosuppressive tumor microenvironment (TME) subtype. Combination therapy with adenosine inhibitors remodels the TME, reversing cetuximab resistance and enhancing anti-PD-1 efficacy in EGFRvIII CRC.Conclusions Our findings identified EGFRvIII-positive CRC as a distinct subtype characterized by adenosine-mediated immunosuppressive TME. Targeting adenosine significantly improved the efficacy of anti-PD-1 in MSS CRC. |
| format | Article |
| id | doaj-art-0ba2f503a1c540e4abf96333f0c88bac |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0ba2f503a1c540e4abf96333f0c88bac2025-08-20T02:13:44ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-010126Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutationJing Wu0Yang Zhao1Min Shi2Yong Li3Yu Jiang4Fei Sun5Jianjun Peng6Jiao Wang7Qiong Huang8Na Huang9Yawen Wang10Yulu Shi11Xiaoxiang Rong12Wangjun Liao13Chunlin Wang14Fangzhen Yao15Chunting Zeng16Bishan Liang17Shaowei Li18Qijing Wu19Zhiqi Yao20Chunhui Gu21Yujing Tan22Department of Oncology, The First People`s Hospital of Foshan, Foshan, Guangdong, ChinaDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaCenter of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaBackground Patients with microsatellite stable (MSS) colorectal cancer (CRC) often display resistance to immunotherapy. Epidermal growth factor receptor (EGFR)-targeted therapies have shown potential in enhancing immunotherapy, yet clinical benefits remain unfulfilled, which may relate to inadequate patient stratification.Methods Circulating tumor cells and tumor tissues were collected from multicenter cohorts of patients with CRC receiving cetuximab to analyze EGFR variant type III (EGFRvIII) expression and immune infiltration. Syngeneic mouse models of EGFRvIII CRC were used to investigate the combined efficacy of adenosine inhibition and antiprogrammed cell death protein 1 (anti-PD-1).Results EGFRvIII mutations are found in about 10% of MSS CRC and are associated with poor response to cetuximab therapy. EGFRvIII-mutated patients with CRC exhibit an adenosine-mediated immunosuppressive tumor microenvironment (TME) subtype. Combination therapy with adenosine inhibitors remodels the TME, reversing cetuximab resistance and enhancing anti-PD-1 efficacy in EGFRvIII CRC.Conclusions Our findings identified EGFRvIII-positive CRC as a distinct subtype characterized by adenosine-mediated immunosuppressive TME. Targeting adenosine significantly improved the efficacy of anti-PD-1 in MSS CRC.https://jitc.bmj.com/content/13/2/e010126.full |
| spellingShingle | Jing Wu Yang Zhao Min Shi Yong Li Yu Jiang Fei Sun Jianjun Peng Jiao Wang Qiong Huang Na Huang Yawen Wang Yulu Shi Xiaoxiang Rong Wangjun Liao Chunlin Wang Fangzhen Yao Chunting Zeng Bishan Liang Shaowei Li Qijing Wu Zhiqi Yao Chunhui Gu Yujing Tan Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation Journal for ImmunoTherapy of Cancer |
| title | Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation |
| title_full | Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation |
| title_fullStr | Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation |
| title_full_unstemmed | Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation |
| title_short | Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation |
| title_sort | targeting adenosine enhances immunotherapy in mss colorectal cancer with egfrviii mutation |
| url | https://jitc.bmj.com/content/13/2/e010126.full |
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