Release of interleukin-1a as a mediator of immune evasion in cancer

PROJECT SUMMARY Cell death is the primary goal of most cancer therapies, but how different forms of cell death regulate the immune response and can be combined with immunotherapies is poorly understood. Inducing necrosis or programmed necrosis are a focus for cancer therapies as these induce loss of membrane integrity and the subsequent release of intracellular molecules that stimulate an inflammatory response, collectively known as alarmins or damage-associated molecular patterns. Surprisingly however, we have found in preliminary studies that programmed necrosis promotes tumor growth and reduces survival in preclinical models by recruiting myeloid cells and creating an immune suppressive microenvironment. These changes are similar to those observed during response to the chemotherapeutic paclitaxel, and are driven by release of the cytokine interleukin-1 alpha. Here we seek to understand how interleukin-1 alpha release alters the immune response during therapy, how release is controlled by the ability of different therapies to activate cell death pathways, and if targeting interleukin-1 alpha can promote response to standard-of-care therapeutics.