Brent A. Hanks, MD, PhD, CLIP Investigator Duke University While checkpoint inhibitor immunotherapies have revolutionized the practice of oncology, these agents have introduced several inflammatory side-effects into the clinic that significantly impact the quality of life and management of cancer patients. With the continued development of immunotherapy combinations with greater potency, it is expected that these immune-related adverse events (irAEs) will only increase in frequency and severity, placing increased stress on our health care system. The field’s understanding of the underlying cause of irAEs remains poor and the therapeutic options to manage these conditions are limited and potentially harmful. Dr. Hanks has found that anti-PD-1 immunotherapy elicits neutrophilic inflammation in both the lung and colonin tumor-bearing hosts, suggesting that a tumor-intrinsic signaling pathway contributes to irAEs. Interestingly, he has further determined that adjuvant anti-PD-1 immunotherapy induces irAEs only in hosts that have previously harbored a resected tumor. Additional studies have shown that genetic silencing of the tumor-intrinsic NLRP3 inflammasome and its downstream mediator, HSP70, eliminates the development of distant organ inflammation during anti-PD-1 immunotherapy. Together, these data suggest that the tumor-intrinsic NLRP3-HSP70 signaling axis modulates distant bone marrow neutrophil progenitors via a mechanism known as trained immunity, thereby sensitizing the host to the development of select irAEs upon exposure to anti-PD-1 immunotherapy. Dr. Hanks proposes a series of experiments to confirm that this pathway triggers neutrophil trained immunity and that this process is necessary for the development of select irAEs in response to checkpoint inhibitor immunotherapy. Dr. Hanks’ work promises to lead to novel pharmacologic targets and biomarkers capable of improving the overall management of irAEs in cancer patients undergoing immunotherapy. Projects and Grants Role of tumor-mediated innate training in the pathogenesis of immune-related adverse events Duke University | All Cancers | 2022
