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

Abstract

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