319 The tumor-intrinsic NLRP3 inflammasome establishes a pulmonary metastatic niche via type II epithelial HSP70/TLR4 signaling and facilitates disease hyperprogression in response to immunotherapy

Background Our understanding of those underlying mechanisms that contribute to metastatic progression in melanoma remains limited. While uncommon, hyperprogression response immunotherapy is likely be an extreme form acquired resistance. Therefore, studies define the these processes are expected provide insight into discovery novel therapeutic targets and predictive biomarkers. We previously demonstrated tumor-intrinsic NLRP3 drives adaptive resistance anti-PD-1 (anti-PD-1) by inducing recruitment polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via upregulation CXCL5. Gain-of-function polymorphisms TLR4 gene have been associated with pulmonary metastases patients. shown HSP70 promote PMN-MDSC chemotaxis stimulation signaling. As a result, we hypothesized tumor inflammasome may also distant disease during establishing long-distance signaling axis mediated HSP70-TLR4 lung. Methods pharmacologically genetically inhibited transgenic BRAFV600E mouse model examine their role before anti-PD-1. An inducible type II epithelial cell-specific knock-out was engineered PMN-MDSCs subsequent Plasma levels were monitored patients undergoing Results Anti-PD-1 significantly increases CXCL2/CXCL5 expression accumulation lungs model. This effect reversed 1) tumor-targeted ablation pharmacologic inhibition but not systemic host NLRP3, 2) Pharmacologic Wnt5a ligand inhibition, 3) tumor-specific HSP70. Inducible suppressed CXCL5 lung Tumor-specific NLRP3/HSP70 lung-specific following Combination primary versus monotherapy. Elevated plasma Abstract 319 Figure 1 Tumor-intrinsic metastasis Conclusions Together, results describe cross-talk mechanism between mediates accentuated (figure 1). Future clinical needed evaluate this tumor-lung NLRP3/HSP70/TLR4/Wnt5a/CXCL5 on checkpoint inhibitor