Immunonutritional Targeting of Cancer via Eicosanoids
Authors: Kelly Abigail , Kipper Franciele C. , Rothenberger Eva , Duncan Madeline , Huang Sung Hee , Hammock Bruce D. , Panigrahy Dipak 
Published: May 2022

Cancer causes widespread mortality via a systemic pro‐inflammatory and dysregulated immune response. Immunotherapy is the front‐line treatment in many cancers with a response rate of approximately 10–30%, although it remains unclear why the response rate is so diverse. Dietary intervention provides an opportunity to optimize the host immune response in cancer patients, however, mechanisms of immunonutritional regulation in cancer are poorly understood. Key components of immune surveillance include the action of cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA4), as certain cancers can utilize CTLA4 to evade immune surveillance. Thus, several monoclonal antibodies targeting CTLA4 are FDA approved. Epidemiological and experimental studies provide evidence that omega‐3 polyunsaturated fatty acids (PUFAs) are beneficial for reducing the risk of cancer, whereas omega‐6 PUFAs can stimulate cancer. Cytochrome P450 epoxygenases represent one branch of PUFA metabolism, generating biologically active omega‐3 epoxy fatty acids (omega‐3 epoxides). Cytochrome P450 epoxygenases convert the omega‐6 PUFA arachidonic acid into epoxyeicosatrienoic acids, which suppress inflammation. Because the half‐life of fatty acid epoxides is rapid, drugs that stabilize their levels by inhibiting soluble epoxide hydrolase (sEHi) are in clinical trials for hyperinflammatory diseases. sEHi may synergize with omega‐3 fatty acids in reducing inflammation and cancer. Since immune checkpoint inhibitors (e.g. CTLA4) can augment cytotoxic T cell responses, we hypothesized that omega‐3 fatty acid supplementation in conjunction with sEHi would enhance immunotherapy in various cancer types. Mice were fed with standard diet, high omega‐6 diet, or high omega‐3 diet for 10 days prior to tumor inoculation and for the duration of the studies. One week following tumor injection, mice were randomized into treatment groups: control, sEHi TPPU (5 mg/kg/day via drinking water), immunotherapy (anti‐CTLA4; 200 µg initial dose, 100 µg Q3D), and TPPU + anti‐CTLA4. Here, we demonstrate in poorly immune responsive tumors (Lewis lung carcinoma (LLC) and B16F10 melanoma) that oral administration of TPPU enhances immunotherapy in mice on a high omega‐3 fatty acid diet to transform “cold” unresponsive tumors into “hot” responsive tumors. Indeed, the combination of TPPU and anti‐CTLA4 resulted in synergistic antitumor activity in mice on the high omega‐3 diet, with 52‐67% inhibition in LLC and B16F10 melanoma compared to control. Anti‐CTLA4 inhibited LLC primary tumor growth in mice on an omega‐3 fatty acid diet. In marked contrast, immune checkpoint blockade (anti‐CTLA4) accelerated LLC growth in mice on an omega‐6 fatty acid diet by 225% compared to control after 15 days of treatment. sEHis alone or in combination with an increased omega‐3 PUFA/omega‐6 PUFA dietary ratio may be a promising new approach to enhance immune checkpoint blockade in cancer. Together, these findings identify omega‐3 epoxides as important regulators of immunotherapy and sEH as a druggable target in cancer.