Novel mechanism of dendritic cell maturation by dying/death tumor cells via photodynamic modulation of type 1 interferon pathway

摘要

During the past decades, a growing body of evidence clearly indicates that type I IFNs (IFN-1) play a pivotal role in naturally occurring and therapy induced immune responses to cancer. In this context, we describe here a novel effect of photodynamic therapy (PDT): besides its potential to induce apoptosis, PDT elicited an autocrine/paracrine activation of IFN-1 pathway. In the current work, B16-OVA cells were sensitized with Me-ALA-induced protoporphyrin IX (PpIX) which preferentially localized in the endoplasmic reticulum prior to irradiation. Subsequent photoactivation of PpIX with red-light irradiation ignificantly stimulated tumor cells to induce autocrine IFN-1 transcription, concurrently with IRF-3 phosphorylation, at levels that were capable of activating STAT1 and enhancing ligand receptor (cGAS) and ISGs (CXCL10, MX1, ISG15) expression. Among the cellular and molecular pathways identified so far, type I IFNs are critical components for the host immune response against tumor, more specifically for the dendritic cell (DC) compartment. In this sense, PDT-treated melanoma cells induced paracrine IFN-1-dependent phenotypic maturation of monocyte-derived dendritic cells (DCs) by enhancing co-stimulatory signals (CD80, MHC-II) and tumor-directed chemotaxis (transwell migration assay). Collectively, our findings strongly demonstrate the effects of a novel danger signal released by cancer cells undergoing PDT on the maturation and activation of DCs, highlighting the potential added value of PDT in adoptive immunotherapy protocols.