USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.

Animals CD8-Positive T-Lymphocytes Cell Line, Tumor Endopeptidases / genetics Endosomal Sorting Complexes Required for Transport / genetics Humans Immunotherapy Mice Neoplasms / drug therapy Programmed Cell Death 1 Receptor / antagonists & inhibitors Tumor Microenvironment Ubiquitin Thiolesterase / antagonists & inhibitors

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
31 03 2022
Historique:
received: 29 07 2021
accepted: 15 03 2022
entrez: 1 4 2022
pubmed: 2 4 2022
medline: 5 4 2022
Statut: epublish

Résumé

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8

Identifiants

DOI: 10.1038/s41467-022-29401-6 PMID: 35361799 PMC: PMC8971425
pubmed: 35361799
doi: 10.1038/s41467-022-29401-6
pii: 10.1038/s41467-022-29401-6
pmc: PMC8971425
doi:

Substances chimiques

Endosomal Sorting Complexes Required for Transport 0
Programmed Cell Death 1 Receptor 0
Endopeptidases EC 3.4.-
USP8 protein, human EC 3.4.19.12
Ubiquitin Thiolesterase EC 3.4.19.12
Usp8 protein, mouse EC 3.4.19.12

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1700

Subventions

Organisme : NCI NIH HHS
ID : P50 CA101942
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA251165
Pays : United States

Informations de copyright

© 2022. The Author(s).

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Auteurs

Wenjun Xiong (W)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Xueliang Gao (X)

Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.

Tiantian Zhang (T)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Baishan Jiang (B)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
Center for Protein Degradation, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0001-6796-9500

Ming-Ming Hu (MM)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.

Xia Bu (X)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.

Yang Gao (Y)

Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.

Lin-Zhou Zhang (LZ)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education and Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 430071, Wuhan, China.

Bo-Lin Xiao (BL)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education and Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 430071, Wuhan, China.

Chuan He (C)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Yishuang Sun (Y)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Haiou Li (H)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
Department of Dermatology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.

Jie Shi (J)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Xiangling Xiao (X)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Bolin Xiang (B)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Conghua Xie (C)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
ORCID: 0000-0001-6623-9864

Gang Chen (G)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education and Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 430071, Wuhan, China.
ORCID: 0000-0003-3332-3511

Haojian Zhang (H)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.

Wenyi Wei (W)

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0003-0512-3811

Gordon J Freeman (GJ)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-7210-5616

Hong-Bing Shu (HB)

Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
ORCID: 0000-0001-9102-3272

Haizhen Wang (H)

Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA. wangha@musc.edu.
ORCID: 0000-0003-3477-8673

Jinfang Zhang (J)

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China. jinfang_zhang@whu.edu.cn.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China. jinfang_zhang@whu.edu.cn.
ORCID: 0000-0001-8487-6007

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Lymphocytes T CD8+ › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Endopeptidases › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Complexes de tri endosomique requis pour le transport › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Tumeurs › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Récepteur-1 de mort cellulaire programmée › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › USP8 inhibition reshapes an inflamed tumor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Ubiquitin thiolesterase › USP8 inhibition reshapes an inflamed tumor...