Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
Cancer Immunol Res. 2020 Jul;8(7):912-925. doi: 10.1158/2326-6066.CIR-19-0877. Epub 2020 Apr 7.
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 CD226CD8 T cells accumulate at the tumor site and have an exhausted phenotype with impaired functionality. In contrast, CD226CD8 tumor-infiltrating T cells possess greater self-renewal capacity and responsiveness. Anti-TIGIT treatment selectively affects CD226CD8 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 CD226CD8 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 CD226CD8 T cells may improve responses to anti-TIGIT therapy.
临床试验正在评估抗 TIGIT 作为单一疗法或与程序性死亡 1 (PD-1)/程序性死亡配体 1 阻断剂联合使用的疗效。TIGIT 阻断是否以及如何与免疫疗法协同作用尚不清楚。在这里，我们表明 CD226CD8 T 细胞在肿瘤部位积累，并具有耗尽表型，功能受损。相比之下，CD226CD8 肿瘤浸润性 T 细胞具有更大的自我更新能力和反应性。抗 TIGIT 治疗通过促进酪氨酸 322 上的 CD226 磷酸化，选择性地影响 CD226CD8 T 细胞。CD226 激动剂抗体介导的 CD226 激活增强了 TIGIT 阻断对 CD8 T 细胞反应的影响。最后，增加胰腺导管腺癌患者 CD226CD8 T 细胞的 mFOLFIRINOX 治疗增强了 TIGIT 或 PD-1 阻断的效果。我们的研究结果表明 CD226 是癌症免疫治疗的预测性生物标志物，并表明增加 CD226CD8 T 细胞的数量可能会改善对 TIGIT 治疗的反应。
