Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Clin Cancer Res. 2023 Jul 14;29(14):2638-2650. doi: 10.1158/1078-0432.CCR-23-0258.
Immunotherapy has led to a fundamental shift in the treatment of several cancers. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) is limited. Understanding the expression of inhibitory immune checkpoint receptors (ICR) by intratumoral T cells may help to unravel their involvement in insufficient T-cell-mediated antitumor immunity.
Using multicolor flow cytometry, we analyzed circulating and intratumoral T cells from blood (n = 144) and matched tumor samples (n = 107) of patients with PDAC. We determined the expression of programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) by CD8+ T-cells, conventional CD4+ T-cells (Tconv) and regulatory T cells (Treg) and their association with T-cell differentiation, tumor reactivity, and cytokine expression. A comprehensive follow-up was used to determine their prognostic value.
Intratumoral T cells were characterized by increased PD-1 and TIGIT expression. Both markers delineated distinct T-cell subpopulations. PD-1+TIGIT- T cells highly expressed proinflammatory cytokines and markers of tumor reactivity (CD39, CD103), whereas TIGIT expression was linked to antiinflammatory and exhausted phenotypes. In addition, the enhanced presence of intratumoral PD-1+TIGIT- Tconv was associated with improved clinical outcomes, while high ICR expression on blood T cells was a significant hazard for overall survival (OS).
Our results uncover the association between ICR expression and T-cell functionality. PD-1 and TIGIT characterized intratumoral T cells with highly divergent phenotypes linked to clinical outcomes, further underscoring the relevance of TIGIT for immunotherapeutic approaches in PDAC. The prognostic value of ICR expression in patient blood may be a valuable tool for patient stratification.
免疫疗法已使几种癌症的治疗发生了根本性转变。然而，其在胰腺导管腺癌（PDAC）中的疗效有限。了解肿瘤内 T 细胞抑制性免疫检查点受体（ICR）的表达情况，可能有助于揭示其在 T 细胞介导的抗肿瘤免疫不足中的作用。
我们使用多色流式细胞术分析了来自 PDAC 患者血液（n=144）和匹配肿瘤样本（n=107）的循环和肿瘤内 T 细胞。我们测定了 CD8+T 细胞、常规 CD4+T 细胞（Tconv）和调节性 T 细胞（Treg）中程序性细胞死亡蛋白 1（PD-1）和 T 细胞免疫受体具有 Ig 和免疫受体酪氨酸抑制基序（ITIM）结构域（TIGIT）的表达情况，并分析其与 T 细胞分化、肿瘤反应性和细胞因子表达的关系。采用全面随访来确定其预后价值。
肿瘤内 T 细胞的特征是 PD-1 和 TIGIT 表达增加。这两种标志物可区分不同的 T 细胞亚群。PD-1+TIGIT-T 细胞高表达促炎细胞因子和肿瘤反应性标志物（CD39、CD103），而 TIGIT 表达与抗炎和耗竭表型相关。此外，肿瘤内 PD-1+TIGIT-Tconv 的存在增加与临床结局改善相关，而血液 T 细胞中 ICR 的高表达是总生存（OS）的显著危害因素。
我们的研究结果揭示了 ICR 表达与 T 细胞功能之间的关联。PD-1 和 TIGIT 可区分具有不同表型的肿瘤内 T 细胞，这些表型与临床结局相关，进一步强调了 TIGIT 在 PDAC 免疫治疗中的重要性。ICR 在患者血液中的表达的预后价值可能是患者分层的有用工具。
