Abstract P031: Enrichment of photodynamically-primed anti-tumor immune infiltrates in pancreatic cancer: Enabling enhanced immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 10%. It poorly responds to conventional cancer treatments. Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. However, in PDAC, even the modest success of ICB is limited to ~1-3% of patients as the majority of patients9 tumors are considered as immunologically ‘9cold99 due to their highly immunosuppressive tumor microenvironment (TME). Photodynamic therapy (PDT) is an FDA approved anti-cancer therapy that utilizes light, a photoresponsive non-toxic chemical called a photosensitizer, and oxygen to generate reactive molecular species that confer direct cytotoxicity or vascular shutdown. PDT alters the TME transiently in a process termed photodynamic priming (PDP), making it more receptive to subsequent therapies, including chemo- and immunotherapy. Previous studies have demonstrated that PDP is capable of affecting both the innate and adaptive immune systems. These immune-stimulatory effects occur through its ability to induce immunogenic cell death via the release of damage-associated molecules (DAMPs) and tumor-associated antigens. In this study, we investigated PDP-induced immunogenicity in PDAC. In an immunocompetent mouse model of PDAC, we evaluated tumor-infiltrating lymphocyte (TIL) enrichment in tumors and ongoing immune responses in mouse spleens/blood from 1h to 120h post-PDP treatment comparing the responses in untreated controls. We observed gradual increases in T and B cell infiltration from 1h to 120h post-PDP where the T cell subset analysis showed an enrichment of CD8⁺ T cells in PDP-treated tumors. These CD8⁺ T cells showed temporal increases in PD1, CTLA4 and TIM3 immune checkpoints suggesting PDP-induced immune priming in the TME. This was further evidenced by the upregulation of DAMPs, including high mobility group box protein-1 and calreticulin in PDP treated tumors. Analyzing spleens of mice, we detected a significant increase in CD11C⁺MHC11^hi dendritic cells from 1h to 24h post-PDP. Also, activation of an adaptive immune response in splenic B cell follicles was noted by the presence of proliferating germinal centers by 120h post-PDP. In addition, evaluating the blood of PDP treated mice, we detected expansion of CD8⁺ effector memory T and natural killer cell populations, signifying PDP-induced systemic immune responses compared to untreated mice. We further investigated how immune cells infiltrate PDP-treated tumors. A reduced formation of blood (CD31⁺) and lymphatic (Lyve-1⁺) vessels post-PDP at 120h was observed. However, decreases in PDL1, collagen and fibroblast activation proteins were observed in PDP-treated tumors at 120h, suggesting mitigation of immunosuppressive mechanisms and enhanced tumor permeability, allowing TIL migration. Our data shows converting immunologically silent PDAC tumors into inflamed ‘9hot99 tumors by triggering not only a local immune infiltration but also enhanced systemic immune responses, ultimately enhances the immunogenicity of pancreatic tumors. Citation Format: Pushpamali De Silva, Mohammad Ahsan Saad, Zhiming Mai, Shazia Bano, Assiris P. Camargo, Tayyaba Hasan. Enrichment of photodynamically-primed anti-tumor immune infiltrates in pancreatic cancer: Enabling enhanced immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P031.