The recent success and expanded use of the checkpoint inhibitor immunotherapies in clinical oncology has resulted in an increased incidence of a variety of immune-related adverse events (irAEs), some of which can have a lasting impact on the lives of our patients. The continued development of adjuvant immunotherapy protocols and more potent immunotherapy combinations such as the ipilimumab/nivolumab regimen is expected to increase the incidence and societal impact of these irAEs. Despite their growing prevalence, the underlying pathogenesis of individual irAEs is poorly understood and our therapeutic management of these conditions remains crude. Using a genetically engineered model of melanoma, we have found that anti-PD-1 antibody (ab) immunotherapy routinely leads to neutrophilic infiltration of the lung parenchyma and colon lamina propria, closely resembling the pathology noted in human checkpoint inhibitor-associated pneumonitis and colitis, respectively. This work further revealed that anti-PD-1 ab treatment of non-tumor-bearing mice eliminates the development of these irAEs, suggesting the presence of a tumor-intrinsic proinflammatory mechanism. As part of this work, we have recently identified a tumor-intrinsic PDL1:NLRP3:HSP70 signaling axis that drives the accumulation of neutrophils in distant organs including the lungs and colon in response to PD-1 blockade. Additional studies have shown that genetic knockout of tumor HSP70 expression and the pharmacological inhibition of the NLRP3 inflammasome suppresses the accumulation of neutrophils in these distant tissues. Based on these findings, we now hypothesize that the tumor NLRP3 inflammasome promotes the development of checkpoint inhibitorassociated colitis and pneumonitis and that NLRP3 represents a promising pharmacological target for suppressing the development of these irAEs. To address this hypothesis, we have generated a transgenic melanoma tissue-specific NLRP3-/- model to examine the role of tumor-intrinsic NLRP3 in the development of checkpoint inhibitor-induced colitis and pneumonitis. Additional studies will address a potential role for this tumor NLRP3 pathway in Th17 differentiation in these distant organ tissues and whether a small molecule inhibitor of NLRP3 would be a superior option over steroids for the management of colitis and pneumonitis in an autochthonous melanoma model undergoing anti-PD-1 ab immunotherapy. We will further utilize tumor tissue and DNA collected from patients undergoing checkpoint inhibitor immunotherapy on an active IRB-approved clinical study to determine if genetic variations of NLRP3 may contribute to the development of these irAEs. Overall, this work will provide unique mechanistic insight into the development of irAEs and identify rational therapeutic strategies and predictive biomarkers for improving the management of patients undergoing immunotherapy.