Inflammasomes in Cancer Progression and Anti-Tumor Immunity

Abstract

The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-inflammatory cytokines vary greatly depending on the cancer type. Here we discuss recent studies highlighting contrasting roles of the inflammasome pathway in curbing versus promoting tumorigenesis. On one hand, the inflammasomes participate in stimulating anti-tumor immunity, but they have also been shown to contribute to immunosuppression or to directly promote tumor cell survival, proliferation, and metastasis. A better understanding of inflammasome functions in different cancers is thus critical for the design of novel cancer immunotherapies.

Keywords: Inflammasome; caspase; immunosuppres-sion; immunotherapy; macrophages; metastasis; pyroptosis; tumor.

FIGURE 1

Diverse mechanisms of inflammasome activation. The activation of the inflammasome by the canonical pathway relies on two signals, the first or the priming signal allowing transcription of inflammasome components, and the second or activating signal triggering the assembly of the complex. The inflammasome scaffolding receptors belong to different families (NLR, ALR and PYRIN), each recognizing different MAMPs or DAMPs. Caspase-1 is central in catalyzing inflammasome functions, cleaving pro-inflammatory cytokines into their bioactive form and gasdermin D (GSDMD) into an N-terminal pore forming domain that elicits pyroptosis. The non-canonical route is mediated by direct binding of LPS or phospholipids to caspase-4/-5 in humans or -11 in mice.

FIGURE 2

Pro-tumoral functions of the inflammasome pathway. (A) The inflammasome, primarily NLRP3, promotes tumor cell survival, proliferation and invasion through IL-1β. Inflammasome-independent functions of AIM2 have also been demonstrated, in which AIM2 controls mitochondrial dynamics and activate oncogenic ERK activation through reactive oxygen species (ROS). (B) The inflammasome can promote tumorigenesis through induction of a chronic inflammatory states. In the intestine, both IL-18 and IL-1β converge on IL-22 production which drives intestinal epithelial cell hyperproliferation. The chronic inflammatory state is also enacted by IL-17 production which recruits granulocytes to amplify the response. In the liver, hepatic injury is associated with AIM2 inflammasome activation both in Kupffer cells and in macrophages of the ascitic fluid. IL-1β in this case promotes hepatocytes hyper-proliferation. In the skin, germ-line mutations in NLRP1 result in chronic inflammation and tumorigenesis. (C) The inflammasomes can indirectly favor tumor development by suppressing anti-tumor immunity. IL-1β was shown to enhance myeloid-derived suppressor cells (MDSC) recruitment to the tumor site and to promote T cell tolerogenic differentiation.

FIGURE 3

Anti-tumoral functions of the inflammasome pathway. (A) The inflammasome can suppress tumor cell proliferation and promotes tissue homeostasis and cell differentiation. (B) Inflammasome activation favors anti-tumor immunity by enhancing NK and CD8 T cell tumorilytic activities. This is primarily mediated by IL-18. Inflammasome triggers enhance the efficacy of immune checkpoint inhibitors. (C) Pyroptotic cell death downstream of inflammasome activation establishes an immunogenic environment through the release of several DAMPs and immunostimulatory molecules. Pyroptosis is initiated by caspase-dependent processing of gasdermins that form pores leading to osmotic lysis of the cell. Certain chemotherapies induce toxicities because of pyroptotic death of healthy cells through gasdermins E cleavage by caspase-3.