GSE200560
Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling and gasdermin D independent secretion of IL-1ß to promote tumor growth
Caspase-1 signaling in myeloid suppressor cells can promote T-cell independent cancer progression, but the regulation of inflammasome signaling within the highly heterogeneous myeloid cells in the tumor milieu remains elusive. To resolve this complexity, scRNA-seq of human head & neck carcinoma identified distinct inflammasome complex genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, NLRP3 sensor and downstream effector IL-1ß transcripts were enriched in multiple monocytic and macrophage subtypes in the TME. In vivo, we showed that NLRP3, and not AIM2, phenocopied the caspase-1/IL-1ß dependent tumor progression. Paradoxically, we found that myeloid-intrinsic caspase-1 signaling within the TME increased myeloid survival without significant intratumoral trafficking as would be predicted from their canonical pyroptotic function. Mechanistically, this myeloid NLRP3/IL-1ß signaling axis promotion of tumor growth was found to be gasdermin D independent. When we probed for the tumor intrinsic factors that regulated NLRP3/IL-1ß signaling, we found that mononuclear phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3 dependent inflammasome signaling to drive IL-1ß secretion and to promote tumor growth. Dynamic RNA velocity analysis of the single cell transcriptomic dataset showed a strong directional flow from efferocytosis gene-sethigh macrophages to an inflammasome gene-sethigh macrophage population.  Cumulatively, we provide a novel inflammasome signaling axis between tumor apoptosis and myeloid cells that characterizes chronic inflammation induced malignancy. Overall design: Comparative gene expression profiling analysis of RNA-seq data for mouse bone marrow-derived macrophages (BMDM) incubated with Annexin V+/PI- Cal27 cells and BMDM that had engulfed AC (PKH26+).