A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal
Abstract Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01545-x |
| _version_ | 1797556075101159424 |
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| author | Min Luo Xueping Wang Shaocong Wu Chuan Yang Qiao Su Lamei Huang Kai Fu Sainan An Fachao Xie Kenneth Kin Wah To Fang Wang Liwu Fu |
| author_facet | Min Luo Xueping Wang Shaocong Wu Chuan Yang Qiao Su Lamei Huang Kai Fu Sainan An Fachao Xie Kenneth Kin Wah To Fang Wang Liwu Fu |
| author_sort | Min Luo |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on “eat-me” signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the “eat-me” signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3β phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and “eat-me” signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy. |
| first_indexed | 2024-03-10T16:57:36Z |
| format | Article |
| id | doaj.art-20237da0e04643d8a399feecb9a9034e |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-10T16:57:36Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-20237da0e04643d8a399feecb9a9034e2023-11-20T11:04:32ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-08-018111310.1038/s41392-023-01545-xA20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signalMin Luo0Xueping Wang1Shaocong Wu2Chuan Yang3Qiao Su4Lamei Huang5Kai Fu6Sainan An7Fachao Xie8Kenneth Kin Wah To9Fang Wang10Liwu Fu11State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterLaboratory Animal Centre, The First Affiliated Hospital of Sun Yat-sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterSchool of Pharmacy, The Chinese University of Hong KongState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterAbstract Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on “eat-me” signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the “eat-me” signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3β phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and “eat-me” signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.https://doi.org/10.1038/s41392-023-01545-x |
| spellingShingle | Min Luo Xueping Wang Shaocong Wu Chuan Yang Qiao Su Lamei Huang Kai Fu Sainan An Fachao Xie Kenneth Kin Wah To Fang Wang Liwu Fu A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal Signal Transduction and Targeted Therapy |
| title | A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal |
| title_full | A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal |
| title_fullStr | A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal |
| title_full_unstemmed | A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal |
| title_short | A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal |
| title_sort | a20 promotes colorectal cancer immune evasion by upregulating stc1 expression to block eat me signal |
| url | https://doi.org/10.1038/s41392-023-01545-x |
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