Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling secretion of IL-1β to promote tumor growth

Abstract

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 population in the tumor milieu remains elusive. To resolve this complexity, single cell transcriptomic profile of Head and Neck Squamous Cell Carcinoma (HNSCC) identified distinct inflammasome-associated genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, the sensor protein, NLRP3, and downstream effector IL-1β transcripts were enriched in discreet monocytic and macrophage subtypes in the TME. We showed that deletion of NLRP3, but not AIM2, phenocopied caspase-1/IL-1β dependent tumor progression in vivo. Paradoxically, we found myeloid-intrinsic caspase-1 signaling increased myeloid survival contrary to what would be predicted from the canonical pyroptotic function of caspase-1. This myeloid NLRP3/IL-1β signaling axis promotion of tumor growth was found to be gasdermin D independent. Mechanistically, we found that phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3-dependent inflammasome signaling to drive IL-1β secretion. Subsequently we showed that NLRP3-mediated IL-1β production drives tumor growth in vivo. Dynamic RNA velocity analysis showed a robust directional flow from efferocytosis gene-set high macrophages to an inflammasome gene-set high macrophage population. We provide a novel efferocytosis-dependent inflammasome signaling pathway which mediates homeostatic tumor cell apoptosis that characterizes chronic inflammation-induced malignancy.

Increased serum caspase-1 in adult-onset Still’s disease

“…However, the cleaved form of caspase-1 was exclusively found in untreated AOSD patients, and it was undetectable among AOSD patients in the remission state receiving immunosuppressive therapy. Pyroptosis, a caspase-1-dependent type of programmed cell death, was recently found to promote the secretion of IL-1b and IL-18 during the in ammatory response [24]. Caspase-1 has also been reported to activate the transcription factor NF-kB independent of its enzymatic activity, which may result in in ammation in vivo [25].…”

The dance of macrophage death: the interplay between the inevitable and the microenvironment

“…Looking for factors that trigger TAMs pyroptosis and have an impact on the TME and immune response, seems to be reasonable. Some studies demonstrate that either cancer cells or tumor-derived molecules can act as DAMPs causing inflammasome activation and pyroptosis in macrophages ( 211 , 212 , 214 , 215 , 225 ). Interestingly, it was also reported that pyroptosis and/or inflammasome activation in TAMs can arise as a side effect of various anticancer therapies ( 214 , 215 , 225 , 226 ) or may be triggered by factors other than DAMPs ( 216 , 227 ).…”

“…Cancer cells can act as factors activating pyroptotic molecules in macrophages. Lang et al demonstrated that efferocytosis of apoptotic cancer cells by TAMs both in vitro and in vivo led to NLRP3 inflammasome activation, caspase-1 processing, and IL-1b secretion in those macrophages (211). This phenomenon resulted in immunosuppression and the promotion of tumor growth.…”

Hijacking homeostasis: Regulation of the tumor microenvironment by apoptosis

“…In addition, "cooperation" between different subroutines of regulated cell death may occur to promote tumor growth, a recent report suggesting that pro-inflammatory efferocytosis of apoptotic cells, caspase 1-induced, gasdermin Dindependent, NLRP3-dependent inflammasome activation and resultant IL-1β production has tumor-promoting properties which may be important in inflammation-driven tumor progression in head and neck squamous cell carcinomas. 301 Other homeostatic programs affecting cell survival and population dynamics such as autophagy 302 and senescence 303 will undoubtedly also play key contributory roles in oncogenesis and progression of malignant diseases in the complex circuitry of cancer tissues alongside apoptosis and other cell death modalities, including regulated, caspase-independent cell death, which can be mediated in certain contexts by EVs. 304 Understanding the integration of the multitude of cell death and environmental signals that determine specific efferocyte responses is hugely challenging (reviewed in 305 ) and one of the most intriguing questions in the apoptosis field is how (and why) so many receptors and opsonins are deployed in efferocytosis.…”

“…The different liver cancer models of HCC, with necrosis promoting chemical carcinogenesis in the former study 299 and apoptosis facilitating the latter 300 also suggest that different routes to development of the same cancer type may be directed by different modes of cell death. In addition, “cooperation” between different subroutines of regulated cell death may occur to promote tumor growth, a recent report suggesting that pro‐inflammatory efferocytosis of apoptotic cells, caspase 1‐induced, gasdermin D‐independent, NLRP3‐dependent inflammasome activation and resultant IL‐1β production has tumor‐promoting properties which may be important in inflammation‐driven tumor progression in head and neck squamous cell carcinomas 301 . Other homeostatic programs affecting cell survival and population dynamics such as autophagy 302 and senescence 303 will undoubtedly also play key contributory roles in oncogenesis and progression of malignant diseases in the complex circuitry of cancer tissues alongside apoptosis and other cell death modalities, including regulated, caspase‐independent cell death, which can be mediated in certain contexts by EVs 304 …”