Westheim Annemarie J F, Dubois Ludwig J, Prades-Sagarra Elia, van de Laak Jella G M, van Mourik Hester, Schuitmaker Lesley, Stoffels Lara M, Yaromina Ala, van Dijk Miriam, van Bergenhenegouwen Jeroen, van Helvoort Ardy, Langen Ramon C J, Shiri-Sverdlov Ronit, Theys Jan
The M-Lab, Department of Precision Medicine, GROW-Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of Genetics and Cell Biology, NUTRIM-Research Institute of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
The M-Lab, Department of Precision Medicine, GROW-Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands.
Cancer Treat Res Commun. 2025 May 15;44:100943. doi: 10.1016/j.ctarc.2025.100943.
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.
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 mm, 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.
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.
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.
新出现的证据表明长链多不饱和脂肪酸（lc-PUFAs）对放疗和抗程序性死亡受体1配体（PD-L1）疗效有积极影响，然而这是否能转化为多模式联合治疗更好的结果仍不清楚。我们假设饮食中的lc-PUFAs可以改善放疗/免疫治疗（RT/IT）联合治疗的结果。
使用流式细胞术在体外测量不同lc-PUFAs在有无放疗情况下对CT26表面PD-L1表达的影响。将接种CT26细胞的具有免疫活性的BALB/cOlaHsd小鼠随机分为不同的基于等热量AIN93M的饮食组，这些饮食富含二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的鱼油、富含花生四烯酸（ARA）的ARASCO油或两者的组合。当肿瘤达到±200立方毫米时，开始照射（2.33 Gy，每日5次）。抗PD-L1（10 mg/kg，腹腔注射，每2天1次，共5次）治疗在1天后开始。研究终点定义为达到起始体积四倍的时间。通过流式细胞术测量对脾细胞毒性CD8+ T细胞数量和活性的影响。
所有测试的lc-PUFAs和照射在体外均上调了PD-L1表达，联合使用时增加更强。与基于大豆油的对照饮食相比，富含n-3 lc-PUFA的鱼油给药可能支持对联合放疗/抗PD-L1治疗的反应性，尽管接近显著水平（风险比0.35 [0.11 - 1.02]，p = 0.053）。未观察到油混合物对肿瘤接种、体重、食物摄入量或脾细胞毒性CD8+ T细胞活化有影响。
给予富含n-3 lc-PUFA的鱼油后，局部肿瘤失败风险有适度降低，这突出了进一步研究的必要性。
