Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

Abstract

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

Microscopic Peritoneal Residual Disease after Complete Macroscopic Cytoreductive Surgery for Advanced High Grade Serous Ovarian Cancer

“…Intraoperative illumination at an appropriate wavelength results in activation of the photosensitizer which is responsible for a photobiological reaction leading to the formation of cytotoxic reactive oxygen species. This results in the death of the tumor cells and a potential abscopal effect mediated by the release of extracellular vesicles with immune-activating properties [ 14 , 39 ]. Its double selectivity (photosensitizer specificity for the tumor and activation controlled by illumination) means there are no distant systemic effects which represents a theoretical advantage over HIPEC.…”

Light emitting fabrics for photodynamic therapy: Technology, experimental and clinical applications

“…CELL‐LEF was already used in experimental studies to evaluate a new folate receptor‐targeted photosensitizer on peritoneal ovarian cancer cells [19] and in four pancreatic adenocarcinoma (ADKP) i cell lines: Capan‐1, Capan‐2, MiapaCa‐2 and Panc‐1. [20]…”

Photodynamic Diagnosis and Therapy for Peritoneal Carcinomatosis: Emerging Perspectives

“…Moreover, active targeting may be explored for the intraperitoneal administration of photosensitizers, which could significantly reduce the systemic causes of PDT-associated morbidity [ 45 , 88 ]. Although some candidate epitopes for molecular targeting have been identified for ovarian cancer [ 89 ], more studies are required to identify suitable targets for PCAR of colorectal, pancreatic and gastric origins. For ALA, biomodulation strategies to increase endogenous PpIX production as described for PDD may have similar relevance to augmenting the efficacy of ALA-PDT.…”

“…The photosensitizer pyropheophorbide conjugated to folate was demonstrated to be effective in binding ovarian cancer cells in a rat model of ovarian PCAR, with a reported tumor-to-normal ratio of 9.6 [ 62 ]. Follow-up studies showed the effective PDT of ovarian and pancreatic cancer cell lines in vitro using this folate-conjugated photosensitizer [ 89 , 91 ], indicating that this targeting strategy may have relevance for pancreatic PCAR as well.…”