Photodynamic Therapy-Induced Cyclooxygenase 2 Expression in Tumor-Draining Lymph Nodes Regulates B-Cell Expression of Interleukin 17 and Neutrophil Infiltration

Abstract

Photodynamic therapy (PDT) is an effective anticancer modality approved by the U.S. Food and Drug Administration (FDA). Antitumor immunity can be augmented during PDT by inducing sterile inflammation in an acute manner, and this process is characterized by interleukin 17 (IL-17)-mediated neutrophil infiltration to tumor-draining lymph nodes (TDLNs). However, the inflammatory factors that influence IL-17 expression in TDLNs are poorly understood. Prior studies have linked the cyclooxygenase 2 (COX2)-driven prostaglandin E₂ (PGE2) pathway to IL-17 expression. Here, we report that an immune-activating PDT regimen (imPDT) induces COX2/PGE2 expression in TDLNs, whereby IL-17 expression is facilitated without corresponding effects on the expression of RORγt, the transcriptional driver of the canonical IL-17 pathway. Pharmacologic inhibition with NS398, a COX2 inhibitor, was utilized to demonstrate that imPDT-induced COX2 regulates RORγt-independent expression of IL-17 by B cells and neutrophil entry into TDLNs. Depletion of B cells prior to imPDT significantly reduced neutrophil entry into TDLNs following treatment, and diminishes the efficacy of imPDT, which is dependent upon antitumor immunity. These findings are suggestive of a novel role for B cells in the augmentation of antitumor immunity by imPDT.