Lymph node macrophages drive immune tolerance and resistance to cancer therapy by expression of the immune-regulatory cytokine IL-33 [scRNA-seq]

Apoptotic cells are immunosuppressive, creating a potential therapeutic barrier in cancer therapy. In this reportwe investigated responses to apoptotic tumor cell phagocytosis (i.e. efferocytosis) after therapy in the tumor draining lymph node (TDLN). Treatment with cisplatin or the BRAF inhibitor PLX4720 caused a significant increase in accumulation of apoptotic tumor material in the TDLN. We identified the primary phagocyte population responsible for clearing dying tumors in the TDLN was medullary sinus macrophages (MSMs). Tumor cell efferocytosis by MSMs induced an immune suppressive transcriptional program distinct from other macrophage or dendritic cell populations in the TDLN. One of the most differentially induced mRNAs in MSMs wasIl33,coding fora potent immune-regulatory cytokine. Administration of neutralizing anti-IL-33 receptor antibodies or deletion ofIl33in MSMs altered tumor responses to therapy with a significant enhancement of anti-tumor activity compared to controls. Mechanistically, IL-33 activated Treg cells in the TDLN with subsequent suppression of CD8+T cell responses. Importantly, combining IL-33 receptor blockade, BRAF inhibitor, and PD-1 blockade significantly improved tumor regression with enhanced, CD8+T cell dependent immunity. Finally, apoptotic tumor cells induced IL-33 expression in human macrophages, IL-33 expression in sentinel lymph nodes positively corresponded with disease stage and negatively correlated with survival in melanoma and breast cancer. Thus, the data identifies an immune response to therapy that abrogates nascent anti-tumor immunity, providing a previously undescribed functional interaction with broad implications for cancer therapy. Overall design: Tumor bearing-mice were treated with Cisplatin, one single (Tx1) or seven consecutive (Tx7) PLX4720 treatments. Tumor or TDLN were then harvested, digested and cell sorted.