5-ALA mediated photodynamic therapy with combined treatment improves anti-tumor efficacy of immunotherapy through boosting immunogenic cell death

Abstract

Photodynamic therapy (PDT) is clinically promising in destructing primary tumors and immunotherapy awakes host immunity to control distant metastases. 5-aminolevulinic acid (5-ALA), a smart photosensitizer, converts into a physiological PDT agent with no dark toxicity in vivo. In this study, we found for the first time 5-ALA-PDT induced colorectal cancer (CRC) cells death by immunogenic cell death (ICD) upon AKT inhibition. Dying cancer cells induced by 5-ALA-PDT efficiently activated bone-marrow derived dendritic cells (BMDCs). Simultaneously, autophagy was observed after AKT inhibition by 5-ALA-PDT. Besides, we found cells died more remarkable by ICD under a circumstance of low occurrence of autophagy. To evaluate the effects of 5-ALA-PDT in vivo, we applied subcutaneous tumor mouse model and delightedly found 5-ALA-PDT induced a systemic antitumor immune response to control both primary tumors and distant metastases. Meanwhile, 5-ALA-PDT enhanced Th1 immunity, leading cytotoxic T lymphocyte response, and raised tumor-specific T cells. Combining with Chloroquine (CQ), 5-ALA-PDT further augmented tumor-specific immunity effects indicating protective role of autophagy. Together, the combination therapy of 5-ALA-PDT and autophagy inhibitor synergistically led to a novel clinical approach and potential ICD-based tumor vaccine for CRC patients.

Keywords: 5-ALA-PDT; AKT; Colorectal cancer; Protective autophagy; Systemic antitumor immune response.