Kelly et al. showed in several murine cancer models that ICI promoted expression of soluble epoxide hydrolase (sEH), which degrades epoxy-fatty acids (EpFAs) known to abate cancer- associated inflammation. Supplementing dietary ω-3 polyunsaturated fatty acids (PUFAs) altered inflammatory endogenous oxylipin levels and inhibited tumor growth. ω-3 PUFA dietary supplementation or genetic modulation of endogenous EpFA levels and/or sEH pharmacologic blockade enhanced ICI efficacy. sEH blockade boosted CD8+ T cell levels and reduced ICI- induced upregulation of inflammatory markers in the TME.
Contributed by Paula Hochman
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.
Author Info: (1) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Cen
Author Info: (1) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (2) Department of Entomology and Nematology, University of California, Davis, CA University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817. Department of Food Science, Purdue University, West Lafayette, IN 47907. (3) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (4) Department of Entomology and Nematology, University of California, Davis, CA University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817. (5) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (6) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (7) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (8) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (9) Department of Entomology and Nematology, University of California, Davis, CA University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817. (10) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (11) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (12) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (13) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. (14) Institute of Systems Biology, Seattle, WA 98109. (15) University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817. Department of Internal Medicine, University of California Davis, CA 95817. (16) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Food Nutrition and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China. (17) Department of Entomology and Nematology, University of California, Davis, CA University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817. (18) Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
