Photodynamic Modulation of Type 1 Interferon Pathway on Melanoma Cells Promotes Dendritic Cell Activation

Abstract

The immune response against cancer generated by type-I-interferons (IFN-1) has recently been described. Exogenous and endogenous IFN-α/β have an important role in immune surveillance and control of tumor development. In addition, IFN-1s have recently emerged as novel DAMPs for the consecutive events connecting innate and adaptive immunity, and they also have been postulated as an essential requirement for induction of immunogenic cell death (ICD). In this context, photodynamic therapy (PDT) has been previously linked to the ICD. PDT consists in the administration of a photosensitizer (PS) and its activation by irradiation of the affected area with visible light producing excitation of the PS. This leads to the local generation of harmful reactive oxygen species (ROS) with limited or no systemic defects. In the current work, Me-ALA inducing PpIX (endogenous PS) was administrated to B16-OVA melanoma cells. PpIX preferentially localized in the endoplasmic reticulum (ER). Subsequent PpIX activation with visible light significantly induced oxidative ER-stress mediated-apoptotic cell death. Under these conditions, the present study was the first to report the in vitro upregulation of IFN-1 expression in response to photodynamic treatment in melanoma. This IFN-α/β transcripts upregulation was concurrent with IRF-3 phosphorylation at levels that efficiently activated STAT1 and increased ligand receptor (cGAS) and ISG (CXCL10, MX1, ISG15) expression. The IFN-1 pathway has been identified as a critical molecular pathway for the antitumor host immune response, more specifically for the dendritic cells (DCs) functions. In this sense, PDT-treated melanoma cells induced IFN-1-dependent phenotypic maturation of monocyte-derived dendritic cells (DCs) by enhancing co-stimulatory signals (CD80, MHC-II) and tumor-directed chemotaxis. Collectively, our findings showed a new effect of PDT-treated cancer cells by modulating the IFN-1 pathway and its impact on the activation of DCs, emphasizing the potential relevance of PDT in adoptive immunotherapy protocols.

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…Therapeutic vaccination of tumor-bearing mice with mo-DCs loaded with RA/IFN-α-tumor cell lysates inhibited tumor growth, which was associated with a systemic Th1-skewed response. Our results were in agreement with the discovery that the activation of DCs mediated by Dox- [116] or photodynamic therapy (PDT)-killed tumor cells [125] is partially mediated by autocrine and/or paracrine pathways that are triggered by IFN-α. Along this line, a variety of stimuli that promote endogenous type I-IFN expression are currently evaluated as an adjuvant strategy in vaccine protocols that aimed at triggering and enhancing immune system activation.…”

“…We demonstrated that the incubation of B16-OVA melanoma cells with Me-ALA as precursor of the endogenous photosensitizer, protoporphyrin IX (PpIX), induced oxidative ER-stress mediated-apoptotic cell death and upregulation of type I IFN expression upon exposure to visible light. DCs pulsed with PDT-treated tumor cells exhibited an enhanced expression of co-stimulatory signals (CD80, MHC-II) and tumor-directed chemotaxis [125]. Overall, accumulating preliminary evidence highlights the future potential relevance of PDT in adoptive immunotherapy protocols.…”

“…Photochemical processes are generated upon irradiation of tumor sites with a PS-exciting light of specific wavelength after administration of the photosensitizer agent (PS). PS toxicity is not appreciated unless oxidative stress occurs in response to its activation [125,141]. In addition to eliciting direct cytotoxic effects [142][143][144][145][146][147] and vascular damage [148], PDT also induces immunological reactions [20,[149][150][151].…”

“…PDT outcome has been associated with the subcellular localization of PSs [146,[152][153][154] and the PDT dose delivered, leading to tumor cell photodamage through four, not mutually exclusive, cell death pathways, such as apoptosis, necrosis, autophagy, and paraptosis, which could differentially stimulate the host immune system [155]. DAMP exposure that was crucial for ICD was reported following photoactivation using several photosensitizers [125,[156][157][158]. The main PDT-generated DAMPs that are involved in ICD include CRT, ATP, HSP90, HSP70, and HMGB1 [84,91,109,125,149,150].…”

“…DAMP exposure that was crucial for ICD was reported following photoactivation using several photosensitizers [125,[156][157][158]. The main PDT-generated DAMPs that are involved in ICD include CRT, ATP, HSP90, HSP70, and HMGB1 [84,91,109,125,149,150]. In a study on skin squamous cell carcinoma by Ji et al, immunogenic apoptotic tumor cells induced by Aminolevulinic acid (ALA) mediated PDT could enhance the antitumor activity of DC-based vaccines in mice.…”