Harnessing innate immunity in cancer therapy and beyond: NLRP3 inflammasome activators
NEUWIRT E. 1,2, AGARINIS C. 3, GORKA O. 1, PARKER C. 3, FARADY C. 3, GROß O. 1,2,4
1 Institute of Neuropathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 2 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany; 3 Novartis Institutes for BioMedical Research, Basel, Switzerland; 4 Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
Cancer and infections are among the leading causes of death and morbidity worldwide. Although the immune system possesses powerful mechanisms to fight cancer and infection, rapidly multiplying pathogens and malignant cells produce counter-mechanisms that thwart immune responses, enabling disease to gain a foothold. Therefore, there is a pressing need for immunostimulatory drugs that can overcome potential immune evasion. The success of adjuvants in vaccinations and immune checkpoint inhibitors in cancer therapy demonstrate the clinical potential of immunostimulants. However, to date, most of the immunomodulatory approaches have focused on enhancing T-cell responses and only a minority of patients with cancer, for example, benefit from immune checkpoint inhibitors. Consequently, to realize the full potential of immunostimulants and to attain greater therapeutic coverage, new therapeutics targeting (other) key players in the immune system are required.
IL-1β is one of the most potent cytokines orchestrating successful immune responses. It is necessary for the TH1 and TH17 responses that underlie immune responses against cancers and against a great number of pathogens. Its bioactivity is strictly controlled by complexes called inflammasomes. The NLRP3 inflammasome is among the most widely expressed and the most important in a diversity of clinical settings, and is therefore considered a prime target for the development of new therapeutics. We set out to identify new small molecule NLRP3 activators that can find clinical application as immune-activating drugs. To this end, we devised a semi-automated screening strategy in primary bone marrow-derived dendritic cells and found a group of novel activators that, surprisingly, engage none of the so far described signaling events upstream of NLRP3 activation. Our ongoing work aims at deciphering the mechanism these molecules engage to activate NLRP3 on the cellular level and, moreover, evaluate their therapeutic potential as immunostimulants turning up the heat on ‘cold’ tumors in various murine tumor models.