Effects of Brief Adjunctive Metformin Therapy in Virologically Suppressed HIV-Infected Adults on Polyfunctional HIV-Specific CD8 T Cell Responses to PD-L1 Blockade
Effects of Brief Adjunctive Metformin Therapy in Virologically Suppressed HIV-Infected Adults on Polyfunctional HIV-Specific CD8 T Cell Responses to PD-L1 Blockade
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DOI：
10.1089/aid.2020.0172
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发表时间：
2020-11-05
影响因子：
1.5
通讯作者：
Ndhlovu, Lishomwa C.
中科院分区：
文献类型：
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作者：
Chew, Glen M.;Padua, Ana Joy P.;Ndhlovu, Lishomwa C.
靶向抑制性免疫检查点受体途径在改善抗癌T细胞应答以消除肿瘤方面已显示出显著的成功。目前正在推行这种免疫战略，以缓解艾滋病毒。二甲双胍在增强程序性细胞死亡-1（PD-1）阻断的功效和恢复抗肿瘤T细胞免疫方面显示出良好的临床结果。此外，已知单核细胞是响应于抗PD-1免疫疗法的无进展生存期的强预测因子。在一项单组临床试验中，我们评估了7名接受联合抗逆转录病毒治疗（cART）的血糖正常、病毒抑制的HIV感染受试者接受二甲双胍治疗8周的免疫学效果。我们使用流式细胞术评估了外周HIV-Gag特异性T细胞对使用抗PD-L1和具有免疫球蛋白和ITIM结构域的抗T细胞免疫受体（TIGIT）单克隆抗体（mAb）的免疫检查点阻断（ICB）的应答的变化以及CD 8 T细胞和单核细胞亚群的变化。研究参与者均为男性，71%（5/7）为高加索人，中位年龄为61岁，CD 4计数为739个细胞/μ L，血浆HIV RNA为1岁。在8周二甲双胍治疗过程中，体外多功能HIV-Gag特异性CD 8 T细胞对抗PD-L1 mAb的应答显著改善（p <0.05）。此外，入组时中等（CD 14（+）CD 16（+）; r = 0.89，p = 0.01）和非经典（CD 14（低）CD 16（+）; r = 0.92，p = 0.01）单核细胞的频率可预测抗HIV CD 8 T细胞对PD-L1阻断的应答程度。总的来说，这些发现强调了8周二甲双胍疗程增加了CD 8 T细胞的多功能性，并且基线单核细胞亚群频率可能是PD-L1阻断疗效的潜在决定因素。这些数据为利用ICB策略增强抗HIV CD 8 T细胞免疫的HIV缓解试验提供了有价值的信息。
Targeting inhibitory immune checkpoint receptor pathways has shown remarkable success in improving anticancer T cell responses for the elimination of tumors. Such immunotherapeutic strategies are being pursued for HIV remission. Metformin has shown favorable clinical outcomes in enhancing the efficacy of programmed cell death-1 (PD-1) blockade and restoring antitumor T cell immunity. Furthermore, monocytes are known to be a strong predictor of progression-free survival in response to anti-PD-1 immunotherapy. In a single-arm clinical trial, we evaluated the immunological effects over an 8-week course of metformin therapy in seven euglycemic, virally suppressed HIV-infected participants on combination antiretroviral therapy (cART). We assessed changes in peripheral HIV-Gag-specific T cell responses to immune checkpoint blockade (ICB) with anti-PD-L1 and anti-T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) monoclonal antibodies (mAbs) and changes in CD8 T cell and monocyte subsets using flow cytometry. Study participants were all male, 71% (5/7) Caucasian, with a median age of 61 years, CD4 count of 739 cells/mu L, and plasma HIV RNA of 1 year. Ex vivo polyfunctional HIV-Gag-specific CD8 T cell responses to anti-PD-L1 mAb significantly improved (p < .05) over the 8-week course of metformin therapy. Moreover, frequencies of both intermediate (CD14(+)CD16(+); r = 0.89, p = .01) and nonclassical (CD14(low)CD16(+); r = 0.92, p = .01) monocytes at entry were predictive of the magnitude of the anti-HIV CD8 T cell responses to PD-L1 blockade. Collectively, these findings highlight that 8-week course of metformin increases the polyfunctionality of CD8 T cells and that baseline monocyte subset frequencies may be a potential determinant of PD-L1 blockade efficacy. These data provide valuable information for HIV remission trials that utilize ICB strategies to enhance anti-HIV CD8 T cell immunity.