Objective: T cell exhaustion is a major mechanism of immune evasion in cancer, characterized by the sustained expression of multiple inhibitory receptors. This study aimed to evaluate the expression of immune checkpoints in peripheral and tumor-infiltrating CD8+T cells from cervical cancer patients.Methods: We enrolled 104 participants: 37 treatment-naïve patients, 36 treated patients, and 31 age-matched healthy donors. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Ten cervical biopsies were collected for tumor-infiltrating lymphocyte (TIL) isolation and paraffin fixation. Immune checkpoint expression was analyzed by multiparametric flow cytometry and immunohistochemistry.Results: In peripheral CD8+T cells, we found a significant upregulation of exhaustion-associated markers PD-1, TIGIT, Tim-3, and LAG-3. In the tumor infiltrating lymphocytes, these same molecules, with the addition of NKG2A, were notably upregulated further. While BTLA and NKG2A showed no systemic changes, NKG2A increased in TILs and BTLA decreased in TILs. The co-expression of PD-1 with TIGIT, Tim-3, LAG-3, and NKG2A was notably enriched between 2- and 6-fold in TILs compared with patient PBMCs. The tumor microenvironment was highly immunosuppressive, characterized by enrichment with PD-1, PD-L1, and TIGIT; TIGIT was notably upregulated in locally advanced versus early-stage tumors.Conclusions: Our findings highlight the strongly immunosuppressive environment of cervical tumors in treatment-naïve patients and the presence of elevated inhibitory checkpoint expression in peripheral blood of both pre- and post-treatment patients. These results underscore the importance of investigating immune regulation within the tumor site itself and suggest that immune checkpoint co-expression may serve as a biomarker of T cell exhaustion and therapeutic resistance. Understanding how treatment alters these pathways could guide rational combination immunotherapies to restore CD8+T cell function in cervical cancer.
目的：T细胞耗竭是癌症免疫逃逸的主要机制，其特征为多种抑制性受体的持续表达。本研究旨在评估宫颈癌患者外周血及肿瘤浸润CD8+T细胞中免疫检查点的表达情况。 方法：研究纳入104名参与者：包括37例初治患者、36例经治患者及31例年龄匹配的健康供者。从所有参与者中分离外周血单个核细胞。收集10例宫颈活检组织用于肿瘤浸润淋巴细胞分离及石蜡包埋固定。通过多参数流式细胞术和免疫组织化学技术分析免疫检查点表达。 结果：在外周CD8+T细胞中，我们发现耗竭相关标志物PD-1、TIGIT、Tim-3和LAG-3显著上调。在肿瘤浸润淋巴细胞中，除上述分子外，NKG2A也呈现显著上调。虽然BTLA和NKG2A未显示系统性变化，但NKG2A在肿瘤浸润淋巴细胞中升高，而BTLA则降低。与患者外周血单个核细胞相比，肿瘤浸润淋巴细胞中PD-1与TIGIT、Tim-3、LAG-3及NKG2A的共表达显著富集2-6倍。肿瘤微环境呈现高度免疫抑制状态，其特征为PD-1、PD-L1和TIGIT的富集；在局部晚期与早期肿瘤中，TIGIT表达显著上调。 结论：我们的研究结果凸显了初治患者宫颈肿瘤的强免疫抑制环境，以及治疗前后患者外周血中抑制性检查点表达的升高。这些发现强调了研究肿瘤局部免疫调节的重要性，并提示免疫检查点共表达可能作为T细胞耗竭和治疗抵抗的生物标志物。理解治疗如何改变这些通路，可为制定合理的联合免疫治疗方案以恢复宫颈癌CD8+T细胞功能提供指导。
肿瘤(癌症)患者之家