Induction of immunological changes induced by photodynamic therapy (PDT) for cancer

Photodynamic therapy (PDT) is a clinically approved procedure for treatment of cancer and certain non-malignant diseases. PDT consists of systemic or topical administration of a photosensitizer (PS) or a PS precursor (prodrug) such as aminolevulinic acid, followed by irradiation of the diseased area with light of wavelengths corresponding to the absorbance band of the PS. When the PS is activated to its excited state by the light, it can react with the surrounding environment and transfer energy to the molecular tissue oxygen, triggering a photochemical reaction and causing cell death. Besides causing direct cytotoxic effects on illuminated cancer cells, PDT is known to cause damage to the tumor vasculature and to induce the release of pro-inflammatory mediators. Previous studies in mouse models and patients have demonstrated that PDT is capable of affecting both innate and adaptive arms of the immune system. It has been shown that besides stimulating tumor-specific cytotoxic T-cells capable to destroy distant untreated tumor cells, PDT can lead to development of anti-tumor memory immunity that potentially prevents the recurrence of cancer. Moreover, several lines of evidence suggest that PDT may also interfere with the immune-suppressive regulatory T cells (Treg). In the present work we thoroughly investigated the intricate immune profile of PDT in both preclinical and clinical studies, involving (1) a colon adenocarcinoma CT26 wild-type tumor mouse model, (2) patients suffering from esophageal squamous cell carcinoma (ESCC) treated with porfimer sodium (Photofrin) and Laser and (3) patients with actinic keratoses (AK), treated with the porphyrin precursor methyl aminolevulinate and red LED light. Our results from the animal model suggested that PDT did not cause any long-term effect on the levels of Treg in the spleen or lymph nodes. However, Treg cells depletion via administration of cyclophosphamide (CY) prior PDT potentiated anti-tumor immunity, leading to increased long-term survival and development of memory immunity. The results obtained from the clinical part of the study indicated that PDT abrogated the suppressive capacity of peripheral Treg from ESCC patients, whereas their Treg levels seemed to be unaffected. Differently, in AK patients neither the level nor the function of peripheral Treg was altered after treatment. Together, this confirms the significant role of the immune system in the response to PDT and enriches the understanding of the role of Treg in PDT-mediated immunological responses. However, the ultimate immunologic outcome upon PDT may depend on the type of cancer and body site treated and vary reliant on the photosensitizer, waveband(s) and/or light doses applied. These results also disclose potential far-reaching clinical implications for the improvement of treatment strategies in patients with cancer (e.g. combining PDT with appropriately designed anti-Treg therapy). (author)