The mechanisms of photodynamic therapy induced anti-tumor immunity
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Photodynamic therapy (PDT) has long been shown to be capable of killing malignant cells, causing shut down of tumor microvasculature, and induction of host immune response. The therapeutic efficacy of PDT is dependent on CD8 + T cells. Activation of tumor-antigen-specific CD8 + T cells requires cross-presentation and cross-priming by dendritic cells (DCs). The cytokine secretion profile of DCs dictates different CD4 + T cell responses, which are critical for CD8 + T cell differentiation and activation. However, the development of CD4 + T cells in the setting of PDT treatment is unclear and controversial. Therefore, to improve PDT efficacy in treating aggressive and metastatic disease, it is imperative to understand the mechanisms of how PDT treatment activates DCs, triggers T cell responses, and the role of responding T cells in PDT efficacy and induction of anti-tumor immunity. We show that PDT-generated tumor cell lysate (PDTTCL) can activate bone marrow-derived dendritic cells (BMDCs) efficiently by upregulation of co-stimulatory molecules and induction of pro-inflammatory cytokines as well as chemokines that are critical mediators for shaping anti-tumor immune response by enhancing CD8 + T cell responses. IL-1β is required for DC cross-priming of interferon (IFN)-γ-producing CD8 + T cells by PDTTCL. PDTTCL-induced IL-1β is produced in a toll-like receptor (TLR)-dependent but NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-inflammasome-independent pathway. In addition, PDTTCL induction of IL-1β precursor synthesis is also dependent upon serine proteases. Our results revealed that PDTTCL induces IL-1β maturation in a novel signaling pathway dependent on membrane-bound protease(s). We found that NF-κB plays a dual role in PDT induction of IL-1β synthesis and activation. Our study contributes to the mechanisms of how PDT enhances tumor cell immunogenicity to promote DC activation, providing the potential means to optimize CD8 + T cell responses and improve clinical PDT efficacy. The mechanisms of how IL-1β contributes to PDT efficacy are not fully understood. In addition to its critical role in DC cross-priming of CD8 + T cells, IL-1β also plays a vital role in Th17 cell differentiation and development. We further investigated the poorly characterized CD4 + T cell responses elicited by PDT. CD4 + T cell lineage differentiation is driven by cytokines generated after DC activation. By examining the cytokine profile of PDTTCL stimulated BMDCs, we found a novel CD4 + Th17 cell response following in situ PDT treatment. The major cytokine secreted by Th17 cells is IL-17, which plays a crucial role in PDT-induced antitumor immunity. A better understanding about how DCs are matured and activated by PDTTCL allows us to further exploit PDT in combination with DC vaccine against aggressive tumor model. We significantly improved PDT efficacy in treating aggressive tumor by combining DC vaccine and TLR8/8 agonist, providing promising strategy using PDT to combat secondary disease in clinics. In PDT combination therapy treated tumor bearing mice, we show that the efficacy of PDT combination therapy is dependent on CD4 + T cells, CD8 + T cells and natural killer (NK) cells. Due to the complex cross-talk of DCs, NK and T cells, we believe it is essential to study the role of them at different stages after PDT to better understand how their roles may change during disease progression, and to optimize PDT efficacy by exploiting them appropriately.