IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer.
IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer.
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IDO 抑制促进三阴性乳腺癌中 V gamma 9V delta 2 T 细胞的抗肿瘤免疫
DOI：
10.3389/fonc.2021.679517
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发表时间：
2021
影响因子：
4.7
通讯作者：
Gao Y
中科院分区：
文献类型：
--
作者：
Li P;Wu R;Li K;Yuan W;Zeng C;Zhang Y;Wang X;Zhu X;Zhou J;Li P;Gao Y
三阴性乳腺癌（TNBC）逃避免疫介导的破坏与免疫抑制反应相关，免疫抑制反应抑制肿瘤浸润CD8和γδ T细胞的激活。与其他乳腺癌亚型相比，TNBC的程序性细胞死亡1-配体1 （PD-L1）和吲哚胺2,3-双加氧酶（IDO）水平较高。但临床研究显示，PD-1/PD-L1抗体治疗TNBC的有效率较低。然而，人类Vγ9Vδ2 T细胞或IDO抑制剂在TNBC治疗中的抗肿瘤反应尚不清楚。在本研究中，我们发现IDO1和PD-L1在TNBC患者中高表达。临床样本分析表明，三阴性乳腺癌患者的v γ - 9v δ2 T细胞已经耗尽。而v - γ - 9v - δ2 T细胞与αPD-L1联用不能进一步增强其体外和体内抗肿瘤作用。然而，Vγ9Vδ2 T细胞联合IDO1抑制剂1-甲基- l-色氨酸（1-MT）或林drostat对MDA-MB-231肿瘤细胞有明显的抑制作用。最后，我们发现IDO1抑制剂通过增强穿孔素的产生来促进T细胞的细胞毒性。这些结果表明，IDO1抑制剂处理的v - γ - 9v - δ2 T细胞在TNBC治疗中的潜在应用。
Triple-negative breast cancer (TNBC) escape from immune-mediated destruction was associated with immunosuppressive responses that dampened the activation of tumor-infiltrating CD8 and γδ T cells. TNBC had a higher level of programmed cell death 1-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO), compared with other breast cancer subtypes. But, clinical studies have revealed that the response rate of PD-1/PD-L1 antibody for TNBC treatment was relatively low. However, the antitumor responses of human Vγ9Vδ2 T cells or IDO inhibitor in TNBC treatment are unknown. In this study, we found that IDO1 and PD-L1 were highly expressed in TNBC patients. Analysis of the clinical samples demonstrated that Vγ9Vδ2 T cells became exhausted in triple-negative breast cancer patients. And Vγ9Vδ2 T cells combined with αPD-L1 could not further enhance their antitumor responses in vitro and in vivo. However, Vγ9Vδ2 T cells combined with IDO1 inhibitor 1-Methyl-L-tryptophan (1-MT) or Lindrostat showed substantial inhibitory effects on MDA-MB-231 tumor cells. Finally, we found that IDO1 inhibitor promoted T cell’s cytotoxicity by enhancing perforin production. These results converged to suggest the potential application of Vγ9Vδ2 T cells treated with IDO1 inhibitor for TNBC therapy.
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影响因子：
11.5
作者：
Brandacher, G;Perathoner, A;Amberger, A
通讯作者：
Amberger, A
影响因子：
28.4
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Mittendorf EA
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Yin, Zhinan
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作者：
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通讯作者：
Kuball, Jurgen
影响因子：
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作者：
Leach, DR;Krummel, MF;Allison, JP
通讯作者：
Allison, JP