Clinical trials are evaluating the efficacy of anti-TIGIT for use as single-agent therapy or in combination with programmed death 1 (PD-1)/programmed death-ligand 1 blockade. How and whether a TIGIT blockade will synergize with immunotherapies is not clear. Here, we show that CD226loCD8+ T cells accumulate at the tumor site and have an exhausted phenotype with impaired functionality. In contrast, CD226hiCD8+ tumor-infiltrating T cells possess greater self-renewal capacity and responsiveness. Anti-TIGIT treatment selectively affects CD226hiCD8+ T cells by promoting CD226 phosphorylation at tyrosine 322. CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT blockade on CD8+ T-cell responses. Finally, mFOLFIRINOX treatment, which increases CD226hiCD8+ T cells in patients with pancreatic ductal adenocarcinoma, potentiates the effects of TIGIT or PD-1 blockade. Our results implicate CD226 as a predictive biomarker for cancer immunotherapy and suggest that increasing numbers of CD226hiCD8+ T cells may improve responses to anti-TIGIT therapy.

中文翻译：

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CD226hiCD8 + T细胞是抗TIGIT免疫疗法的先决条件。

临床试验正在评估抗TIGIT用作单药治疗或与程序性死亡1（PD-1）/程序性死亡配体1阻断剂联用的功效。TIGIT阻断剂将如何以及是否与免疫疗法协同作用尚不清楚。在这里，我们显示CD226loCD8 + T细胞在肿瘤部位积聚，并具有功能受损的疲惫表型。相反，CD226hiCD8 +肿瘤浸润性T细胞具有更大的自我更新能力和响应能力。抗TIGIT处理通过促进酪氨酸322处的CD226磷酸化来选择性地影响CD226hiCD8 + T细胞。CD226激动剂抗体介导的CD226活化增强了TIGIT阻断对CD8 + T细胞反应的作用。最后，mFOLFIRINOX治疗可增加胰腺导管腺癌患者的CD226hiCD8 + T细胞，增强了TIGIT或PD-1阻断的作用。我们的结果暗示CD226可作为癌症免疫治疗的预测性生物标志物，并表明CD226hiCD8 + T细胞数量的增加可能会改善对抗TIGIT治疗的反应。