CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma.

Aged Animals Antineoplastic Agents, Immunological / pharmacology Carcinoma, Renal Cell / genetics Cell Line, Tumor Chemotherapy, Adjuvant / methods DNA Mutational Analysis Disease Models, Animal Disease-Free Survival Female Follow-Up Studies Humans Kidney Neoplasms / genetics Male Middle Aged Mutation Neoplasm Recurrence, Local / epidemiology Nephrectomy Primary Cell Culture Prognosis Receptors, CCR5 / metabolism Tumor Microenvironment / drug effects Tumor Suppressor Proteins / genetics Ubiquitin Thiolesterase / genetics

immunology oncology urology

Journal

Journal for immunotherapy of cancer

ISSN: 2051-1426

Titre abrégé: J Immunother Cancer

Pays: England

ID NLM: 101620585

Informations de publication

Date de publication:
04 2020

Historique:

accepted: 31 03 2020

entrez: 7 5 2020

pubmed: 7 5 2020

medline: 27 5 2021

Statut: ppublish

Résumé

Patients with BRCA1-associated protein 1 (BAP1)-mutant clear cell renal cell carcinoma (ccRCC) have worse prognosis. C-C chemokine receptor 5 (CCR5) plays an important role in ccRCC development and its expression is elevated in BAP1-mutant tumors. 533 patients with ccRCC from The Cancer Genome Atlas cohort and 797 patients with ccRCC from the Shanghai cohort were enrolled. In vitro and in vivo studies were conducted with human ccRCC tumors and murine tumor models. The association between BAP1 and CCR5 or its ligands was assessed by immunohistochemistry, flow cytometry, real-time PCR and ELISA. Survival was compared between different subpopulations of patients using Kaplan-Meier curve. Therapeutic effect of CCR5 blockade was validated using human ccRCC tumors and murine models. Expression of CCR5 and its ligands were elevated in BAP1-mutant patients with ccRCC. High CCR5 expression was indicative of poor prognosis in BAP1-low group of patients. CCR5 blockade prolonged the survival of tumor-bearing mice, resulting in enhanced cytotoxicity of T cells and antigen presentation of dendritic cells but repressed immune checkpoint expression. CCR5 ligands could recruit CCR5 CCR5 in BAP1-mutant ccRCC results in an immune-suppressive microenvironment. Targeting CCR5 could provide a potential therapeutic benefit for patients. NCT01358721, CA209-009.

Sections du résumé

BACKGROUND

METHODS

533 patients with ccRCC from The Cancer Genome Atlas cohort and 797 patients with ccRCC from the Shanghai cohort were enrolled. In vitro and in vivo studies were conducted with human ccRCC tumors and murine tumor models. The association between BAP1 and CCR5 or its ligands was assessed by immunohistochemistry, flow cytometry, real-time PCR and ELISA. Survival was compared between different subpopulations of patients using Kaplan-Meier curve. Therapeutic effect of CCR5 blockade was validated using human ccRCC tumors and murine models.

RESULTS

Expression of CCR5 and its ligands were elevated in BAP1-mutant patients with ccRCC. High CCR5 expression was indicative of poor prognosis in BAP1-low group of patients. CCR5 blockade prolonged the survival of tumor-bearing mice, resulting in enhanced cytotoxicity of T cells and antigen presentation of dendritic cells but repressed immune checkpoint expression. CCR5 ligands could recruit CCR5

CONCLUSIONS

CCR5 in BAP1-mutant ccRCC results in an immune-suppressive microenvironment. Targeting CCR5 could provide a potential therapeutic benefit for patients.

TRIAL REGISTRATION NUMBER

NCT01358721, CA209-009.

Identifiants

DOI: 10.1136/jitc-2019-000228 PMID: 32371459 PMC: PMC7228663

pubmed: 32371459

pii: jitc-2019-000228

doi: 10.1136/jitc-2019-000228

pmc: PMC7228663

pii:

doi:

Substances chimiques

Antineoplastic Agents, Immunological 0

BAP1 protein, human 0

CCR5 protein, human 0

CCR5 protein, mouse 0

Receptors, CCR5 0

Tumor Suppressor Proteins 0

Ubiquitin Thiolesterase EC 3.4.19.12

Banques de données

ClinicalTrials.gov

['NCT01358721']

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Informations de copyright

Déclaration de conflit d'intérêts

Competing interests: None declared.

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