The innate immune receptor, NLRX1, functions as a tumor suppressor by reducing colon tumorigenesis and key tumor-promoting signals

Abstract

Abstract NLR (NOD-like receptor) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1−/− mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including NF-kB, MAPK, STAT3 and IL-6. The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+colon tumorigenesis, cellular proliferation, NF-kB, MAPK, STAT3 activation and IL-6 levels. Application of anti-IL6R antibody therapy reduced tumor burden, increased survival and reduced STAT3 activation in Nlrx1−/−Apcmin/+mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a personalized therapeutics for colon cancers with reduced NLRX1.