Modulation of the Immune Response by IL-17 Following Photodynamic Therapy
Brackett, Craig Michael
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Photodynamic therapy (PDT) is a Food and Drug Administration (FDA)-approved local cancer treatment that can be curative of early stage and palliative of advanced-stage disease. A hallmark of PDT is the induction of sterile inflammation characterized by increased expression of pro-inflammatory cytokines and rapid entry of N1 neutrophils into TDLNs. N1 neutrophil presence within TDLNs has been shown to be critical for the activation of CD8 + T cells and the induction of anti-tumor immunity. The mechanism controlling N1 neutrophil entry into TDLNs remains unclear. Blood-borne N1 neutrophils are excluded from entering lymph nodes across vascular portals termed high endothelial venules (HEVs) due to lack of expression of the CCR7 homeostatic chemokine receptor. Prior evidence that IL-17 promotes N1 neutrophil emigration to sites of infection via induction of MIP-2/CXCL2 and KC/CXCL1 inflammatory chemokines raised the question of whether IL-17 contributes to chemokine-dependent trafficking in TDLNs. We report that non-hematopoietic expression of IL-17RA regulates N1 neutrophil accumulation in TDLNs following induction of sterile inflammation by PDT. We further show that N1 neutrophil entry in TDLNs occurs through L-selectin-dependent binding to HEVs and is supported by preferential interactions between CXCR2 and MIP-2, but not KC. MIP-2 induction in TDLNs was mapped in a linear pathway downstream of IL-17RA-dependent induction of IL-1β. These results define a novel IL-17-dependent mechanism promoting N1 neutrophil delivery across HEVs in TDLNs during acute inflammatory responses. We further investigated whether the lack of N1 neutrophils in TDLNs of Il17ra -/- mice post PDT correlated with reduced generation of anti-tumor immunity post PDT. We report that the efficacy of PDT is dependent upon IL-17RA. IL-17 is required for increasing the number of activated CD8 + T cells post PDT but does not affect T cell function. Reduced total numbers of activated T cells in Il17ra -/- mice post PDT may be explained by the apparent role of IL-17 in regulating T cell proliferation and accumulation to TDLNs post treatment. Fewer total numbers of activated CD8 + T cells post PDT leads to fewer CD8 + T eff memory cells and diminished tumor-specific memory recall response. Although non-hematopoietic expression of IL-17RA regulates N1 neutrophil accumulation to the TDLN, expression of IL-17RA by hematopoietic cells is required for CD8 + T cell activation post PDT. Thus, the requirement for hematopoietic expression of IL-17RA for T cell activation suggests that interactions of IL-17RA on APCs by IL-17 may increase the migration of APCs to the TDLN. These results demonstrate that IL-17 contributes to the generation of anti-tumor immunity by regulating CD8 + T cell proliferation and accumulation to the TDLNs post PDT. In contrast to the enhancement of anti-tumor immunity by IL-17 post PDT, IL-6 negatively regulates anti-tumor immunity and decreases PDT efficacy. IL-6 regulates expression of the pro-apoptotic protein BAX resulting in reduced apoptosis in post-PDT treated tumors. Thus, the induction of IL-6 and IL-17 by PDT acts as a double-edged sword. A fine balance exists between IL-6 and IL-17 for PDT regimens that generate an inflammatory response designed to optimally enhance anti-tumor immunity.