Abstract B51: Photodynamic therapy modulates extracellular matrix and induces anti-tumor immune responses in an orthotopic pancreatic cancer model
Authors: Saad Mohammad A , Morala Jimena Nicolás , Mai Zhiming , Hasan Tayyaba 
Published: December 2022

Abstract
PDAC has a low 5-year survival rate of ~10% which has not changed much over the past few decades. Desmoplasia, characterized by deposition of extracellular matrix (ECM) elements, such as collagen and hyaluronic acid (HA) is a hallmark feature of the PDAC (pancreatic ductal adenocarcinoma) microenvironment. The mechanical and biological barrier imposed by high desmoplastic content in PDAC tumors makes them refractory to conventional chemotherapeutics and is a major cause of immune cell exclusion, observed in these tumors, resulting in a dismal response to immunotherapy. Only ~1-3% of PDAC patients respond to immune checkpoint therapy, highlighting the need for novel therapeutic strategies to overcome treatment resistance observed in these tumors. In this regard, photodynamic therapy (PDT) and the associated phenomenon of photodynamic priming (PDP) has been demonstrated to overcome various physiological and mechanical barriers, in pre-clinical models of desmoplastic PDAC, and sensitizing them to subsequent therapies. PDT involves the administration of a relatively non-toxic molecule, referred to as photosensitizer, which can be activated by external irradiation and in the presence of molecular oxygen results in the formation of reactive molecular species (RMS). While the RMS generated during the process can induce immunogenic cell death it has been recently demonstrated to modulate ECM thereby permeabilizing the tumors to drugs and allowing for increased immune cell infiltration. In this study, using a syngeneic immunocompetent KPC PDAC model, we demonstrate that a single dose of Visudyne® (an FDA approved photosensitizer formulation) with irradiation at 100 J/cm2, significantly reduced tumor volume and increased survival (Median survival 36.5 days for the control group versus 43 days for the PDT-treated group). Mechanistically, apart from inducing cytotoxicity, PDT significantly reduced Hyaluronic acid content in these tumors leading to an enhanced immune cell infiltration. Importantly, regions of Hyaluronic acid depletion, 72 h post-PDT, were found to have a significantly higher CD4+ and CD8+ T-cell infiltration characterized by CD3+CD4+CD45+ and CD3+CD8a+CD45+ markers, respectively. Our ongoing work is aimed at studying the effect of combining immune checkpoint therapy with PDT for improving survival in these PDAC mouse models. Collectively, these results demonstrate the potential of PDT to not only induce immunogenic cell death in PDAC tumors, but also positively modulate tumor ECM components resulting in an enhanced immune cell infiltration. While the role of ECM in PDAC is extremely complex with both tumor restraining and tumor promoting roles, the potential of a single clinically approved treatment modality, PDT, in modulating ECM and enhancing immunogenicity warrants further investigation in a tumor type which has not benefitted much from conventional therapies.
Citation Format: Mohammad A Saad, Jimena Nicolás Morala, Zhiming Mai, Tayyaba Hasan. Photodynamic therapy modulates extracellular matrix and induces anti-tumor immune responses in an orthotopic pancreatic cancer model [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B51.