CD137 agonism enhances anti-PD1 induced activation of expanded CD8+ T cell clones in a neoadjuvant pancreatic cancer clinical trial
Janelle M. Montagne, Jacob T. Mitchell, Joseph A. Tandurella, Eric S. Christenson, Ludmila Danilova, Atul Deshpande, Melanie Loth, Dimitrios N. Sidiropoulos, Emily F. Davis-Marcisak, Daniel Bergman, Qingfeng Zhu, Hao Wang, Luciane T. Kagohara, Logan L Engle, Benjamin Green, Alexander V. Favorov, Won Jin Ho, Su Jin Lim, Rui Zhang, Li Pan, Jessica Gai, Guanglan Mo, Sarah Mitchell, Rulin Wang, Ajay Vaghasia, Wenpin Hou, Yao−Zhong Xu, Jacquelyn W. Zimmerman, Jennifer H. Elisseeff, Srinivasan Yegnasubramanian, Robert A. Anders, Elizabeth M. Jaffee, Lei Zheng, Elana J. Fertig
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.