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Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy.

ABSTRACT: Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

SUBMITTER: Gao Y

PROVIDER: S-EPMC7484128 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy.

Gao Yang Y Nihira Naoe Taira NT Bu Xia X Chu Chen C Zhang Jinfang J Kolodziejczyk Aleksandra A Fan Yizeng Y Chan Ngai Ting NT Ma Leina L Liu Jing J Wang Dong D Dai Xiaoming X Liu Huadong H Ono Masaya M Nakanishi Akira A Inuzuka Hiroyuki H North Brian J BJ Huang Yu-Han YH Sharma Samanta S Geng Yan Y Xu Wei W Liu X Shirley XS Li Lei L Miki Yoshio Y Sicinski Piotr P Freeman Gordon J GJ Wei Wenyi W

Nature cell biology 20200824 9

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the en ...[more]

PMID: 32839551

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Project description:Immunotherapies have led to substantial changes in cancer treatment and have been a persistently popular topic in cancer research because they tremendously improve the efficacy of treatment and survival of individuals with various cancer types. However, only a small proportion of patients are sensitive to immunotherapy, and specific biomarkers are urgently needed to separate responders from nonresponders. Mismatch repair pathways play a vital role in identifying and repairing mismatched bases during DNA replication and genetic recombination in normal and cancer cells. Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host. Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis. Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors. To date, the anti-programmed cell death-1 inhibitor pembrolizumab has been approved for mismatch repair deficiency/microsatellite instability-high refractory or metastatic solid tumors, and nivolumab has been approved for colorectal cancer patients with mismatch repair deficiency/microsatellite instability-high. This is the first time in the history of cancer therapy that the same biomarker has been used to guide immune therapy regardless of tumor type. This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death-ligand 1/programmed cell death-1, and the recent advances in predicting immunotherapy efficacy.

Dataset Information

Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy.

Publications

Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy.

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