Photodynamic Therapy–Induced Immunosuppression in Humans Is Prevented by Reducing the Rate of Light Delivery

Abstract

Photodynamic therapy (PDT) of non-melanoma skin cancers currently carries failure rates of 10-40%. The optimal irradiation protocol is as yet unclear. Previous studies showed profound immunosuppression after PDT, which may compromise immune-mediated clearance of these antigenic tumors. Slower irradiation prevents immunosuppression in mice, and may be at least as effective as high-fluence-rate PDT in preliminary clinical trials. The photosensitizers 5-aminolaevulinic acid and/or methyl aminolaevulinate were applied to discrete areas on the backs of healthy Mantoux-positive volunteers, followed by narrowband red light irradiation (632 nm) at varied doses and fluence rates. Delayed type hypersensitivity (Mantoux) reactions were elicited at test sites and control sites to determine immunosuppression. Human ex vivo skin received low- and high-fluence-rate PDT and was stained for oxidative DNA photolesions. PDT caused significant, dose-responsive immunosuppression at high (75 mW cm(-2)) but not low (15 or 45 mW cm(-2)) fluence rates. DNA photolesions, which may be a trigger for immunosuppression, were observed after high-fluence-rate PDT but not when light was delivered more slowly. This study demonstrates that the current clinical PDT protocol (75 mW cm(-2)) is highly immunosuppressive. Simply reducing the rate of irradiation, while maintaining the same light dose, prevented immunosuppression and genetic damage and may have the potential to improve skin cancer outcomes.

Red versus blue light illumination in hexyl 5-aminolevulinate photodynamic therapy: the influence of light color and irradiance on the treatment outcomein vitro

“…41,42 PDT was shown to trigger immune suppression at high irradiances but immune stimulation at low irradiances in normal skin. 22 This is interesting from the perspective of different death modes observed at high and low irradiance in our study. Stimulation of antitumor immunity after PDT is recognized, but the details/trigger mechanisms are still discussed.…”

“…Thus, high irradiance was found to be immunosuppressive, whereas a similar total dose administered using lower irradiance was not immunosuppressive. 22 In the present study, we have used five different human cancer cell lines and compared the overall PDT efficiency when using HAL-induced PpIX as photosensitizer activated by light of either 410 or 624 nm. We observed substantial differences among the cell types in their sensitivities to light.…”

Platelets, photosensitizers, and PDT

“…This is opposite to the effects of radio-and chemotherapy and surgery which are immunosuppressive [91]. However, recent reports on non melanoma skin cancer ALA treatment have indicated that PDT induced immunosuppression can occur and can be prevented by using lower light doses [92].…”

Tumor Microenvironment as a Determinant of Photodynamic Therapy Resistance

“…Light delivery at lower fluence rate can inhibit PDT-induced inflammation, under the condition that the full dose of an effective treatment regimen is delivered at the low rate [9]. Interestingly, low fluence rate can also abrogate PDT-induced immunosuppression [22]. In a rodent peritoneal model of ovarian cancer, Estevez et al [23] showed that even a small decrease in fluence rate from 30 to 20 mW/cm 2 for hexaminolaevulinatemediated PDT of equal treatment length led to increases in the frequency of fullthickness necrosis of tumor nodules.…”