NLRP3 Inflammasome Mediated Interleukin-1β Production in Cancer-Associated Fibroblast Contributes to ALA-PDT for Cutaneous Squamous Cell Carcinoma.

Abstract

BackgroundLong-term tumor control following PDT is a result of its direct effect on tumor and vasculature in combination with induction of inflammatory-reactions upregulating the immune system. When PDT induces necrosis of tumors and vascular system, an immune cascade can be initiated to release all kinds of cytokines including IL1β. This further leads to the activation of inflammatory-cells and hence death of tumor cells.MethodsUltraviolet irradiation was used to induce cSCC mice model, gene chip was used to screen inflammatory cytokines, qPCR, ELISA and implanted tumor mice model were used to verify the changes and important role of interleukin-1β, and WB preliminarily explored the production mechanism of interleukin-1β.ResultsInflammatory cytokines and receptors transcript screening identify IL1r1 as the top4. After ALA-PDT, IL1r1 and IL1β increased in patients’ biopsies, principally in mesenchymal cells. In vivo, the inhibition of ALA-PDT on tumor growth of cutaneous squamous cell carcinoma (cSCC) mice in the group with intralesional injection of anti-IL1β mAb or caspase1-inhibitor was significantly weaker than the control groups. Furthermore, NLRP3-inflammasome and p-p65/p65 were elevated after ALA-PDT mediated IL1β production in cancer-associated-fibroblasts.DiscussionBy means of activating NLRP3-inflammasome with IL1β production in CAFs, PDT stimulates local acute-inflammatory-response, which further promotes PDT effect for cSCC.