Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase
Abigail G. Kelly, Weicang Wang, Eva Rothenberger, Jun Yang, Molly M. Gilligan, Franciele Kipper, Ahmed Attaya, Allison Gartung, Sung Hee Hwang, Michael Gillespie, Rachel L. Bayer, Katherine Quinlivan, Kimberly L. Torres, Sui Huang, Nicholas Mitsiades, Haixia Yang, Bruce D. Hammock, Dipak Panigrahy
Abstract
Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation. Here, we demonstrate that systemic treatment with ICI induces sEH expression in multiple murine cancer models. Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH inhibition, both alone and in combination, significantly enhance anti-tumor activity of ICI in these models. Notably, pharmacological abrogation of the sEH pathway alone or in combination with ICI counter-regulates an ICI-induced pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous EpFA levels through dietary supplementation or sEH inhibition may represent a unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.