The ω-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid Enhances NK-Cell Antitumor Effector Functions

作者全名：Wu, Shuting; Peng, Hongyan; Li, Songyang; Huang, Lanlan; Wang, Xiangyu; Li, Yana; Liu, Yongjie; Xiong, Peiwen; Yang, Qinglan; Tian, Kunpeng; Wu, Weiru; Pu, Rongxi; Lu, Xiulan; Xiao, Zhenghui; Yang, Jian; Zhong, Zhaoyang; Gao, Yuan; Deng, Yafei; Deng, Youcai

作者地址：[Wu, Shuting; Peng, Hongyan; Li, Songyang; Wang, Xiangyu; Li, Yana; Liu, Yongjie; Xiong, Peiwen; Yang, Qinglan; Lu, Xiulan; Xiao, Zhenghui; Deng, Yafei] Hunan Childrens Hosp, Pediat Res Inst, Hunan Prov Key Lab Childrens Emergency Med, Changsha, Hunan, Peoples R China; [Wu, Shuting; Peng, Hongyan; Li, Songyang; Wang, Xiangyu; Li, Yana; Liu, Yongjie; Xiong, Peiwen; Yang, Qinglan; Lu, Xiulan; Xiao, Zhenghui; Deng, Yafei] Cent South Univ, Affiliated Childrens Hosp, Xiangya Sch Med, Changsha, Peoples R China; [Huang, Lanlan; Deng, Yafei] Univ South China, Sch Pediat, Hengyang Med Sch, Changsha, Peoples R China; [Tian, Kunpeng; Wu, Weiru; Pu, Rongxi; Deng, Youcai] Army Med Univ, Coll Pharm & Lab Med Sci, Dept Clin Hematol, Chongqing, Peoples R China; [Yang, Jian] Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 3, Chongqing, Peoples R China; [Zhong, Zhaoyang] Fifth Peoples Hosp Chongqing, Chongqing, Peoples R China; [Gao, Yuan] Shanxi Med Univ, Translat Med Res Ctr, Taiyuan, Peoples R China; [Deng, Youcai] Army Med Univ, Chongqing 400038, Peoples R China; [Deng, Yafei] Hunan Childrens Hosp, Changsha 410007, Peoples R China; [Gao, Yuan] Shanxi Med Univ, Taiyuan 030001, Peoples R China

通信作者：Deng, YC (通讯作者)，Army Med Univ, Chongqing 400038, Peoples R China.; Deng, YF (通讯作者)，Hunan Childrens Hosp, Changsha 410007, Peoples R China.; Gao, Y (通讯作者)，Shanxi Med Univ, Taiyuan 030001, Peoples R China.

来源：CANCER IMMUNOLOGY RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001239166900006

JCR分区：Q1

影响因子：8.1

年份：2024

卷号：12

期号：6

开始页：744

结束页：758

文献类型：Article

关键词：　

摘要：DHA has direct growth suppressing effects on tumour cells. The authors show it also has an immunomodulatory effect, limiting tumour growth by enhancing NK-cell IFN gamma production and cytotoxicity, likely by upregulating mitochondrial activity via the PGC-1 alpha pathway. omega-3 polyunsaturated fatty acids (PUFA) are known to directly repress tumor development and progression. In this study, we explored whether docosahexaenoic acid (DHA), a type of omega-3 PUFA, had an immunomodulatory role in inhibiting tumor growth in immunocompetent mice. The number of natural killer (NK) cells but not the number of T or B cells was decreased by DHA supplementation in various tissues under physiologic conditions. Although the frequency and number of NK cells were comparable, IFN gamma production by NK cells in both the spleen and lung was increased in DHA-supplemented mice in the mouse B16F10 melanoma tumor model. Single-cell RNA sequencing revealed that DHA promoted effector function and oxidative phosphorylation in NK cells but had no obvious effects on other immune cells. Using Rag2-/- mice and NK-cell depletion by PK136 antibody injection, we demonstrated that the suppression of B16F10 melanoma tumor growth in the lung by DHA supplementation was dependent mainly on NK cells. In vitro experiments showed that DHA directly enhanced IFN gamma production, CD107a expression, and mitochondrial oxidative phosphorylation (OXPHOS) activity and slightly increased proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) protein expression in NK cells. The PGC-1 alpha inhibitor SR-18292 in vitro and NK cell-specific knockout of PGC-1 alpha in mice reversed the antitumor effects of DHA. In summary, our findings broaden the current knowledge on how DHA supplementation protects against cancer growth from the perspective of immunomodulation by upregulating PGC-1 alpha signaling-mediated mitochondrial OXPHOS activity in NK cells.

基金机构：National Natural Science Foundation of China (NSFC) [2020YFA0113500, 2019YFA0111200]; National Key Research and Development Project [82304511, 81922068, 81703521, 81900055]; National Natural Science Foundation of China [B202302078468]; Scientific Research Project of the Hunan Provincial Health Commission [2023JJ30320, 2023JJ40349, 202122JJ40197, 2021JJ40274]; Natural Science Foundation of Hunan Province [2019, 2021]; Science Foundation of Hunan Children's Hospital [cstc2021jcyj-jqX0006]; Chongqing Science and Technology Commission of China; Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG) [CTONG-YC20210104]; Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer

基金资助正文：This study was supported by funding from the National Key Research and Development Project (No. 2020YFA0113500 to Yo. Deng and No. 2019YFA0111200 to Y. Gao), the National Natural Science Foundation of China (82304511 to S. Wu, No. 81922068 to Yo. Deng, No. 81703521 to Ya. Deng, and No. 81900055 to H. Peng) and the Scientific Research Project of the Hunan Provincial Health Commission (No. B202302078468 to S. Wu). This study was also supported by funding from the Natural Science Foundation of Hunan Province (No. 2023JJ30320 to Ya. Deng; 2023JJ40349 to S. Wu; No. 202122JJ40197 to P. Xiong; and No. 2021JJ40274 to H. Peng). This work was also supported by funding from the Science Foundation of Hunan Children's Hospital (2019 and 2021). This study was supported by grants from the Chongqing Science and Technology Commission of China (cstc2021jcyj-jqX0006 to Yo. Deng) and Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG), Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (CTONG-YC20210104 to Z. Zhong). We wish to thank Pro. Li Liping for strong spiritual support. The authors would like to thank Solutex GC, SL, for providing the OMEGATEX 0076-TG DHA oil.