Neoadjuvant radioimmunotherapy in pancreatic cancer enhances effector T cell infiltration and shortens their distances to tumor cells

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_H1, and T_H17, 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.