A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target.

Autor:	Freeman ZT; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.; Unit for Laboratory Animal Medicine, Medical School.; Rogel Cancer Center, and., Nirschl TR; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Hovelson DH; Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA., Johnston RJ; Bristol-Myers Squibb, Redwood City, California, USA., Engelhardt JJ; Bristol-Myers Squibb, Redwood City, California, USA., Selby MJ; Bristol-Myers Squibb, Redwood City, California, USA., Kochel CM; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Lan RY; Bristol-Myers Squibb, Redwood City, California, USA., Zhai J; Department of Biostatistics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA., Ghasemzadeh A; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Gupta A; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Skaist AM; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Wheelan SJ; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Jiang H; Rogel Cancer Center, and.; Department of Biostatistics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA., Pearson AT; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA., Snyder LA; Oncology Discovery, Janssen R&D, Spring House, Pennsylvania, USA., Korman AJ; Bristol-Myers Squibb, Redwood City, California, USA., Tomlins SA; Rogel Cancer Center, and.; Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Michigan Center for Translational Pathology, Department of Pathology, and.; Department of Urology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA., Yegnasubramanian S; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.; Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Drake CG; Department of Oncology and.; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.; Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.; Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Mar 02; Vol. 130 (3), pp. 1405-1416.
DOI:	10.1172/JCI128672
Abstrakt:	Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB-expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB-expressing Tregs represents a strategy with potential activity across cancer types.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu