3,3'-Diindolylmethane improves antitumor immune responses of PD-1 blockade via inhibiting myeloid-derived suppressor cells.
3,3'-Diindolylmethane improves antitumor immune responses of PD-1 blockade via inhibiting myeloid-derived suppressor cells.
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3,3-二吲哚基甲烷通过抑制骨髓源性抑制细胞改善 PD-1 阻断的抗肿瘤免疫反应
DOI：
10.1186/s13020-022-00638-z
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发表时间：
2022-06-30
期刊：
影响因子：
4.9
通讯作者：
Chen, Jiangning
中科院分区：
文献类型：
--
作者：
Sun, Qi;Xiao, Lin;Cui, Zhiying;Yang, Yaping;Ma, Junting;Huang, Zhen;Zhang, Junfeng;Chen, Jiangning
关键词：
靶向程序性细胞死亡蛋白1（PD-1）的免疫检查点抑制剂已经获得了令人鼓舞的结果，但由于存在多种免疫抑制因子，如骨髓源性抑制细胞（MDSC），一部分肿瘤患者对抗PD-1治疗无效。中药或药用植物的天然产物可以增强免疫力，可能有助于癌症的免疫治疗。3，3 ′-二吲哚甲烷（DIM）作为十字花科植物的消化代谢产物，已广泛应用于化疗，但其对肿瘤免疫治疗的影响尚不清楚。在这里，我们研究了DIM对MDSC的功能，并检查了DIM与PD-1抗体结合对小鼠肿瘤的治疗效果。采用流式细胞术、Western blot和qRT-PCR方法研究DIM对MDSCs的抑制作用及其机制。在乳腺癌和黑色素瘤肿瘤的小鼠模型中评估DIM对PD-1抗体的癌症免疫疗法的治疗效果。DIM通过下调miR-21的表达，激活PTEN/PIAS 3-STAT 3通路，对MDSCs产生抑制作用。MDSC的连续转移削弱了DIM的治疗效果，表明DIM的抗肿瘤活性可能是由于MDSC的抑制。此外，在乳腺癌和黑色素瘤肿瘤的小鼠模型中，添加DIM可以通过促进T细胞应答来增强PD-1抗体的治疗效果，从而抑制肿瘤生长。总体而言，基于抗PD-1抗体和DIM联合治疗的策略可能为癌症免疫治疗提供新的途径。富含DIM前体的十字花科植物的饮食可能对接受抗PD-1治疗的癌症患者有益。在线版本包含补充材料，可通过10.1186/s13020-022-00638-z获得。
Immune checkpoint inhibitors that target programmed cell death protein 1 (PD-1) have obtained encouraging results, but a fraction of tumor patients failed to respond to anti-PD-1 treatment due to the existence of multiple immune suppressive elements such as myeloid-derived suppressor cells (MDSCs). Traditional Chinese medicine or natural products from medicinal plants could enhance immunity and may be helpful for cancer immunotherapy. As a digestive metabolite from cruciferous plants, 3,3′-diindolylmethane (DIM) has been widely used in chemotherapy, but its influence on cancer immunotherapy remains unclear. Here we investigate the function of DIM on MDSCs and examine the therapeutic effects of DIM in conjunction with PD-1 antibody against mouse tumors. Flow cytometry analysis, Western blot analysis and qRT-PCR assay were used to examine the inhibitory effects and mechanisms of DIM on MDSCs in vitro and in vivo. The therapeutic effects of DIM on cancer immunotherapy by PD-1 antibody were evaluated in mouse models of breast cancer and melanoma tumor. DIM exerted the inhibitory effect on MDSCs via downregulating miR-21 level and subsequently activating PTEN/PIAS3-STAT3 pathways. Adoptive transfer of MDSCs impaired the therapeutic effects of DIM, indicating that the antitumor activity of DIM might be due to the suppression of MDSCs. Furthermore, in mouse models of breast cancer and melanoma tumor, the addition of DIM can enhance the therapeutic effect of PD-1 antibody through promoting T cells responses, and thereby inhibiting tumor growth. Overall, the strategy based on the combination treatment of anti-PD-1 antibody and DIM may provide a new approach for cancer immunotherapy. Cruciferae plants-rich diet which contains high amount of DIM precursor may be beneficial for cancer patients that undergo the anti-PD-1 treatment. The online version contains supplementary material available at 10.1186/s13020-022-00638-z.
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影响因子：
5.2
作者：
Ishfaq M;Pham T;Beaman C;Tamayo P;Yu AL;Joshi S
通讯作者：
Joshi S
影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
5.6
作者：
Connolly EL;Sim M;Travica N;Marx W;Beasy G;Lynch GS;Bondonno CP;Lewis JR;Hodgson JM;Blekkenhorst LC
通讯作者：
Blekkenhorst LC
影响因子：
7.9
作者：
Heo, Jae-Rim;Lee, Geum-A;Choi, Kyung-Chul
通讯作者：
Choi, Kyung-Chul
DOI：
10.1126/science.aar4060
发表时间：
2018-03-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ribas A;Wolchok JD
通讯作者：
Wolchok JD