Photodynamic priming with red light triggers adaptive immune responses in a pancreatic cancer mouse model

Abstract

The poor response of pancreatic ductal adenocarcinoma (PDAC) to treatment, including immunotherapy, is attributed to its tumor microenvironment (TME). An ongoing challenge is the desmoplastic and immunosuppressed TME that evades immune surveillance. Here, we investigate transient modulation of the TME to overcome immunosuppression using a light-activated process, termed photodynamic priming (PDP). As a first step, this study captures the temporal dynamics of variations in immune infiltrates and subsequent immune responses in the TME, spleen, and blood of the KPC mouse model of PDAC post-PDP. In response to PDP, there were transient increases in tumor infiltrating lymphocytes (TIL) in tumors. The TIL population post-PDP includes an enrichment of CD8⁺ T cells, accompanied by temporal increases in PD-1, CTLA-4, and TIM-3 immune checkpoints on both CD8⁺ T and CD4⁺ T cells. Significant increases in CD11C⁺MHC-11⁺ dendritic cells and proliferating lymphocytes are observed in the spleen within several hours post-tumor PDP, suggesting initiation of adaptive immune responses. These observations are followed by an expansion of CD44⁺CD62^-CD8⁺ effector memory T cells in the blood over several days as evidence of a systemic immune response. Post-PDP TME alterations also included the reduced formation of blood (CD31⁺) and lymphatic (Lyve-1⁺) vessels as well as decreases in PD-L1 and collagen content. Collectively, these data suggest that PDP helps to mitigate immunosuppressive mechanisms and promote enhanced tumor permeability. The temporal dynamics of the processes elucidated here pave the way to develop strategies in future work for combined PDP-immunotherapy utilizing the immune checkpoint expression dynamics for precision therapy.

Keywords: Desmoplasia; Immune checkpoint blockade; Immunogenic cell death; Immunotherapy; Photodynamic therapy; Tumor-infiltrating lymphocytes.