RT Journal Article SR Electronic T1 A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e001866 DO 10.1136/jitc-2020-001866 VO 8 IS 2 A1 Weinan Guo A1 Jinyuan Ma A1 Sen Guo A1 Huina Wang A1 Sijia Wang A1 Qiong Shi A1 Lin Liu A1 Tao Zhao A1 Fengfan Yang A1 Shuyang Chen A1 Jianru Chen A1 Jianhong Zhao A1 Chen Yu A1 Xiuli Yi A1 Yuqi Yang A1 Jingjing Ma A1 Qingrong Ni A1 Guannan Zhu A1 Tianwen Gao A1 Chunying Li YR 2020 UL http://jitc.bmj.com/content/8/2/e001866.abstract AB 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.