Freeman et al. identified checkpoint signatures expressed by tumor-infiltrating Tregs purified from multiple human cancer types. RNAseq analysis of sorted tumor Tregs revealed a conserved checkpoint signature containing 4-1BB that was selective for tumor Tregs, compared to peripheral Tregs and other CD4+ T cell types. Depleting 4-1BB in mouse tumor models was highly effective in reducing tumor burden and prolonging survival. TCGA analysis revealed that high numbers of 4-1BB+ Tregs and low CD8+ T cell numbers correlated with worse survival outcomes, suggesting that depleting Tregs with anti-4-1BB could have activity across multiple cancers.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Unit for Laboratory Animal Medici
Author Info: (1) 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. (2) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. (3) Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA. (4) Bristol-Myers Squibb, Redwood City, California, USA. (5) Bristol-Myers Squibb, Redwood City, California, USA. (6) Bristol-Myers Squibb, Redwood City, California, USA. (7) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. (8) Bristol-Myers Squibb, Redwood City, California, USA. (9) Department of Biostatistics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA. (10) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. (11) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. (12) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. (13) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. (14) Rogel Cancer Center, and. Department of Biostatistics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA. (15) Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA. (16) Oncology Discovery, Janssen R&D, Spring House, Pennsylvania, USA. (17) Bristol-Myers Squibb, Redwood City, California, USA. (18) 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, Ann Arbor, Michigan, USA. (19) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (20) Department of Oncology and. Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
