Inhibition of photodynamic therapy induced‑immunosuppression with aminolevulinic acid leads to enhanced outcomes of tumors and pre‑cancerous lesions (Review)

Photodynamic therapy (PDT) is a treatment option for tumors and pre-cancerous lesions, but it has immunosuppressive side effects that limit its effectiveness. Recent studies suggest that PDT-mediated immunosuppression occurs through a cyclooxygenase type 2 (COX-2) mediated pathway that leads to increases in regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which act as negative regulators of immune responses. Given this pathway, there are three main methods to block immunosuppression: i) Inhibiting the proliferation of Tregs, which can be achieved with the administration of cyclophosphamide or inhibitors of indoleamine 2,3-dioxygenase 1, an activator of Tregs; ii) inhibiting MDSCs by reducing hypoxia around the tumor to create an unfavorable environment or administering all-trans-retinoic acid, which converts MDSCs to a non-immunosuppressive state; and iii) inhibiting COX-2 through selective or non-selective COX-inhibitors. In the present review article, strategies that have shown increased efficacy of PDT in treating tumors and pre-cancerous lesions by blocking the immunosuppressive side effects are outlined and discussed. Abbreviations: PDT, photodynamic therapy; ROS, reactive oxygen species; ALA, 5-aminolevulinic acid; MAL, methyl aminolevulinate; PplX, protoporphyrin IX; 5-FU, 5-fluorouracil; DNFB, dinitrofluorobenzene; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells; HSV, herpes simplex virus; TGF-[beta], transforming growth factor [beta]; IL-10, interleukin-10; PAF, platelet-activating factor; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; IFN[gamma], interferon [gamma]; IDO, indoleamine 2,3-dioxygenase; ATRA, all trans retinoic acid; ATP, adenosine triphosphate; PM-IR780-Met, platelet membranes as nano-carriers to co-encapsulate metformin and IR780; NSAID, nonsteroidal anti-inflammatory drugs; COX-1, cyclooxygenase-1 Key words: photodynamic therapy, immunosuppression, precancerous lesions, squamous cell carcinoma, actinic keratosis, pharmacologic therapy