CD137 agonism enhances anti-PD1 induced activation of clonally expanded CD8+ T cells in a neoadjuvant pancreatic cancer clinical trial

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 to guide design of more effective combinations. We provide a reference single-cell dataset from PDAC-infiltrating T cell and monocyte subsets 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 a CD137 agonist. Tumor infiltrating leukocytes analyzed two weeks post neoadjuvant therapy revealed shifts in CD8+ T cell activation as well as cytoskeletal and extracellular matrix (ECM)-interacting components with Cy/GVAX and anti-PD1. Addition of a CD137 agonist was associated with increased abundance of activated and clonally expanded CD8+ T cells with distinct perturbations in cytoskeletal and ECM components. Furthermore, a new computational method to compare ligand-receptor networks between patients from different treatment arms found that CD137 agonism is associated with immunosuppressive TREM2 signaling in tumor associated macrophages (TAMs) that corresponds to changes in cell metabolism, function, and ECM interactions. Altogether 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. Single-cell RNA-seq and single-cell TCR-seq data were collected from tumor-infiltrating leukocytes in primary human pancreatic cancer tumors following neoadjuvant immunotherapy. Treatments included seven patients receiving cyclophosphamide (Cy)/GVAX alone (Arm A), four patients receiving the combination of Cy/GVAX and anti-PD1 (nivolumab, Arm B), and four patients receiving Cy/GVAX, anti-PD1, and CD137 agonist (urelumab, a human IgG4 agonistic monoclonal antibody, Arm C). *************************************************************** Raw files for human/patient samples are being made available in dbGaP (https://www.ncbi.nlm.nih.gov/gap/) for controlled access to the personally identifiable sequence data. *************************************************************** dbGaP (phs003002.v2.p1)