Immunomodulatory effects of photodynamic therapy for skin cancer: Potential strategies to improve treatment efficacy and tolerability.

Skin cancer, including melanoma and nonmelanoma variants, accounts for the majority of cancer diagnoses in the United States each year and is increasingly the focus of research on treatment and prevention. Photodynamic therapy (PDT) is a well-established, nonscarring treatment for nonmelanoma cancers such as early squamous precancers (actinic keratoses, AK), squamous carcinoma in situ, and superficial basal cell carcinoma (BCC). PDT can be painful during illumination and has relatively poor efficacy for thick lesions. However, these disadvantages could be ameliorated if newly recognized PDT effects on immunity were fully understood and harnessed. In this review, we highlight basic and translational studies on effects that locally administered PDT exerts on the immune system. On the one hand, PDT stimulates an anti-tumor immune response observable as peritumoral infiltration of innate and adaptive immune cells and activation of cytotoxic T cells both locally and in circulating blood. On the other hand, PDT generates systemic immunosuppression mediated by the release of subcellular microvesicle particles (MVP); the latter may be blocked by using acid sphingomyelinase (aSMase) inhibitors. The ultimate goal must be to balance two opposing forces, that is, to limit PDT-induced immunosuppression while promoting PDT-induced regression of tumors so as to favor a long-term anti-tumor immune response.