Medullary sinus macrophages limit cancer therapy efficacy by an efferocytosis-induced IL-33/ST2 axis in the tumor-draining lymph node.

Abstract Cell death is a fundamental aspect of tissue homeostasis that can expose potentially immunogenic cell components must be removed to prevent inflammatory autoimmunity. We have shown immune suppression in response apoptotic phagocytosis (a process called efferocytosis) dependent on tissue-resident macrophages (Mf). Indeed, if we disrupt Mf regulatory responses post-efferocytosis, the same cells induce inflammation suggesting dying are key determinant tolerance. predict resident lining lymphatic sinus inside lymph nodes responsible for tolerance against tumor cells. Using our mouse melanoma model, observed after either chemotherapy or targeted therapy subpopulation TDLN, medullary (MSM), avidly phagocytosed and acquired tolerogenic phenotype. RNA sequencing analysis revealed MSM rapidly exclusively induced expression alarmin IL-33 as opposed other dendritic populations TDLN. Importantly, genetic deletion Il33 using novel MSM-specific model (MSM-IL33ko) generated by laboratory, blockade receptor ST2 with IgG, transformed both prolonged, enhanced control reduced cancer reoccurrence. Functionally, MSM-derived triggered accumulation activation T TDLN which then migrated limiting intratumoral CD8 +T function. Thus, data previously undescribed death-induced mechanism anti-cancer immunity efficacy. CIHR, NIH