A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma
Background The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistan...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001866.full |
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| author | Lin Liu Chen Yu Jingjing Ma Weinan Guo Jinyuan Ma Sen Guo Huina Wang Sijia Wang Qiong Shi Tao Zhao Fengfan Yang Shuyang Chen Jianru Chen Jianhong Zhao Xiuli Yi Yuqi Yang Qingrong Ni Guannan Zhu Tianwen Gao Chunying Li |
| author_facet | Lin Liu Chen Yu Jingjing Ma Weinan Guo Jinyuan Ma Sen Guo Huina Wang Sijia Wang Qiong Shi Tao Zhao Fengfan Yang Shuyang Chen Jianru Chen Jianhong Zhao Xiuli Yi Yuqi Yang Qingrong Ni Guannan Zhu Tianwen Gao Chunying Li |
| author_sort | Lin Liu |
| collection | DOAJ |
| description | Background The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.Methods The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.Results We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden.Conclusions Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade. |
| format | Article |
| id | doaj-art-3f4b3b63f302476db29d827a3a50e984 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3f4b3b63f302476db29d827a3a50e9842024-11-11T01:45:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001866A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanomaLin Liu0Chen Yu1Jingjing Ma2Weinan Guo3Jinyuan Ma4Sen Guo5Huina Wang6Sijia Wang7Qiong Shi8Tao Zhao9Fengfan Yang10Shuyang Chen11Jianru Chen12Jianhong Zhao13Xiuli Yi14Yuqi Yang15Qingrong Ni16Guannan Zhu17Tianwen Gao18Chunying Li191 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China2 Critical Care Medicine, Tumor Hospital of Harbin Medical University, Harbin, China2 Department of Nursing, Ningbo Medical Centre Lihuili Hospital, Ningbo, Zhejiang, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China3 Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1Guangdong Second provincial General Hospital, Department of Rheumatology and Immunology, Guangzhou, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Neurorehabilitation, China Rehabilitation Research Center, Beijing, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, China1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi`an, Shaanxi, ChinaSchool of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaBackground The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.Methods The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.Results We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden.Conclusions Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.https://jitc.bmj.com/content/8/2/e001866.full |
| spellingShingle | Lin Liu Chen Yu Jingjing Ma Weinan Guo Jinyuan Ma Sen Guo Huina Wang Sijia Wang Qiong Shi Tao Zhao Fengfan Yang Shuyang Chen Jianru Chen Jianhong Zhao Xiuli Yi Yuqi Yang Qingrong Ni Guannan Zhu Tianwen Gao Chunying Li A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma Journal for ImmunoTherapy of Cancer |
| title | A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma |
| title_full | A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma |
| title_fullStr | A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma |
| title_full_unstemmed | A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma |
| title_short | A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma |
| title_sort | a20 regulates the therapeutic effect of anti pd 1 immunotherapy in melanoma |
| url | https://jitc.bmj.com/content/8/2/e001866.full |
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