Dietary enrichment with n-3 lc-PUFA-rich fish oil improves preclinical outcome of radiotherapy and anti-PD-L1 combination treatment

Background: Emerging evidence suggests a positive impact of long-chain polyunsaturated fatty acids (lc-PUFAs) on radiotherapy and anti-PD-L1 efficacy, however whether this translates into better outcomes in multimodality combination treatments remains unclear. We hypothesized that dietary lc-PUFAs can improve the outcome of RT/IT combination treatment. Methods: Effects of different lc-PUFAs on CT26 surface PDL-1 expression were measured in vitro in absence or presence of radiotherapy using flow cytometry. Immunocompetent BALB/cOlaHsd mice, inoculated with CT26 cells, were randomized across different isocaloric AIN93M-based diets enriched with either eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) rich fish oil, arachidonic acid (ARA) rich ARASCO oil or combination of both. When tumors reached ±200 mm3, irradiation (2.33 Gy, QD5) was started. anti-PD-L1 (10 mg/kg, i.p., Q2Dx5) treatment started 1 day later. Study endpoint was defined as time to reach four times starting volume. Effects on splenic cytotoxic CD8+ T-cell number and activity was measured by flow cytometry. Results: All lc-PUFAs tested and irradiation, upregulated PD-L1 expression in vitro with a stronger increase when combined. n-3 lc-PUFA-rich fish oil administration may support responsiveness to combined RT/anti-PD-L1 therapy, compared to control diet based on soybean oil, although borderline significant (hazard ratio 0.35 [0.11–1.02], p = 0.053). No effects of the oil blends were observed on tumor take, body weight, food intake or activation of splenic cytotoxic CD8+ T-cells. Conclusion: A modest reduction in the risk of local tumor failure was observed upon n-3 lc-PUFA-rich fish oil administration, highlighting a need for further research.