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 E 2 (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. 2, where l is the longest axis of the tumor and w is the axis

Single‐Component Dual‐Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase‐2 Inhibition for Lung Cancer and Spinal Metastasis

“…In addition to directly killing tumor tissues, some studies have reported that PDT exhibits a powerful function in immune activation, known as immune‐activating PDT (imPDT). [ 5 ] However, with in‐depth studies, apparent drawbacks of PDT that adversely affect the immune microenvironment have been uncovered, which may severely impair its antitumor efficacy. [ 5 , 6 ] Thus, a more effective combination treatment using PDT for cancer should identify critical gene changes and related products induced in tumor cells capable of conferring immune escape in the tumor microenvironment (TME).…”

“…PDT significantly increases cyclooxygenase 2 (COX‐2) expression. [ 5 , 6 ] COX‐2, known as prostaglandin G/H synthase‐2, is typically low‐expressed in normal tissues but high‐expressed in many human tumors. [ 7 ] It converts arachidonic acid to the endogenous peroxidation intermediate PGH2, which is further modified to prostaglandins via prostaglandin synthase.…”