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

• DOI: 10.1126/sciadv.adk1827
• Publication Date: 2024-02-07T19:36:41Z
• Authors: Junke Wang; Jessica Gai; Tengyi Zhang; Nan Niu; Hanfei Qi; Dwayne L. Thomas; Keyu Li; Tao Xia; Christina Rodriguez; Rose Parkinson; Jennifer Durham; Thomas McPhaul; Amol K. Narang; Robert A. Anders; Arsen Osipov; Hao Wang; Jin He; Daniel A. Laheru; Joseph M. Herman; Valerie Lee; Elizabeth M. Jaffee; Elizabeth D. Thom...; Qingfeng Zhu; Lei Zheng
• Keywords: Pancreatic Neoplasms; 03 medical and health sciences; 0302 clinical medicine; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Humans; Biomedicine and Life Sciences; CD8-Positive T-Lymphocytes; Radioimmunotherapy; Neoadjuvant Therapy

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.