Montagne, Mitchell, and Tandurella et al. analyzed scRNAseq of tumor-infiltrating leukocytes from patients receiving an allogeneic PDAC vaccine with anti-PD-1 or with anti-PD-1 plus CD137 agonist. GVAX combined with anti-PD-1 increased CD8+ T cell activation, cytoskeletal remodeling, and ECM interaction. Adding CD137 agonists further boosted clonal CD8+ T cell abundance and activation, but also induced TREM2-mediated immunosuppressive signaling in TAMs, which is linked to altered metabolism and ECM remodeling. Anti-PD-1 induced transcriptomic alterations in TAM metabolism, functions, and ECM interactions, which CD137 agonists further enhanced.
Contributed by Shishir Pant
ABSTRACT: Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist. Treatment with GVAX and anti-PD-1 led to increased CD8(+) T cell activation and expression of cytoskeletal and extracellular matrix (ECM)-interacting components. Addition of CD137 agonist increased abundance of clonally expanded CD8(+) T cells and increased immunosuppressive TREM2 signaling in tumor associated macrophages (TAMs), identified by comparison of ligand-receptor networks, corresponding to changes in metabolism and ECM interactions. These findings associate therapy with GVAX, anti-PD1, and CD137 agonist with enhanced CD8(+) T cell function while inducing alternative immunosuppressive pathways in patients with PDAC.
Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins Univers
Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD, USA. (3) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (9) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD, USA. (10) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11) Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (13) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (14) Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Moscow, RF, Russia. (17) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (18) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (19) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (22) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (23) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (24) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (25) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (26) Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. (27) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (28) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (29) Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (30) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. InHealth Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (31) Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (32) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (33) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (34) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA.
