Neoadjuvant radioimmunotherapy in pancreatic cancer enhances effector T cell infiltration and shortens their distances to tumor cells
Jun-Ke Wang, Jessica Gai, Tengyi Zhang, Nan Niu, Hanfei Qi, Dwayne L. Thomas, Keyu Li, Tao Xia, Christina M. Rodriguez, Rose Parkinson, Jennifer N. Durham, Thomas McPhaul, Amol Narang, Robert A. Anders, Arsen Osipov, Hao Wang, Jin He, Daniel A. Laheru, Joseph M. Herman, Valerie Lee, Elizabeth M. Jaffee, Elizabeth D. Thompson, Qingfeng Zhu, Lei Zheng
Abstract
Radiotherapy is hypothesized to have an immune-modulating effect on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) to sensitize it to anti–PD-1 antibody (a–PD-1) treatment. We collected paired pre- and posttreatment specimens from a clinical trial evaluating combination treatment with GVAX vaccine, a–PD-1, and stereotactic body radiation (SBRT) following chemotherapy for locally advanced PDACs (LAPC). With resected PDACs following different neoadjuvant therapies as comparisons, effector cells in PDACs were found to skew toward a more exhausted status in LAPCs following chemotherapy. The combination of GVAX/a–PD-1/SBRT drives TME to favor antitumor immune response including increased densities of GZMB + CD8 + T cells, T H 1, and T H 17, which are associated with longer survival, however increases immunosuppressive M2-like tumor-associated macrophages (TAMs). Adding SBRT to GVAX/a–PD-1 shortens the distances from PD-1 + CD8 + T cells to tumor cells and to PD-L1 + myeloid cells, which portends prolonged survival. These findings have guided the design of next radioimmunotherapy studies by targeting M2-like TAM in PDACs.