Interleukin-1 (IL-1) and the inflammasome in cancer.

Numerous preclinical and clinical studies have demonstrated the significant contribution of inflammation to the development and progression of various types of cancer. Inflammation in the tumor microenvironment mediates complex interactions between innate immunity, adaptive immunity, microbiomes and stroma, and ultimately alters the overall fitness of tumor cells at multiple stages of carcinogenesis. Malignancies are known to arise in areas of chronic inflammation and inflammation in the tumor microenvironment (often called tumor-promoting inflammation) is believed to allow cancer cells to evade immunosurveillance while promoting genetic instability, survival and progression. Among the strongest data suggesting a causal role for inflammation in cancer come from the recent CANTOS trial which demonstrated that interleukin-1β (IL-1β) inhibition with canakinumab leads to a significant, dose-dependent decrease in incident lung cancer. This observation has launched a series of additional clinical studies to understand the role of IL-1β and the inflammasome in cancer, and the clinical utility of IL-1β inhibition in different stages of lung cancer. In this article we will review recent data implicating IL-1β signaling and its upstream regulator NLRP3 in both solid tumor and hematologic malignancies. We will discuss the key preclinical observations and the current clinical landscape, and describe the pharmacologic tools which will be used to evaluate the effects of blocking tumor-promoting inflammation clinically.