肿瘤细胞治疗研究
英文原题：T Cell Exhaustion in the Cervical Cancer Tumor Microenvironment: PD-1 Overexpression and Co-Expression with TIGIT, Tim-3, LAG-3, and NKG2A.
方法：我们招募了104名参与者：37名未接受治疗的患者、36名已接受治疗的患者和31名年龄匹配的健康供者。
目的：T细胞耗竭是癌症免疫逃逸的主要机制，其特征是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和肿瘤浸润CD8+ T细胞中免疫检查点的表达。 方法：我们纳入了104名参与者：37名初治患者、36名经治患者和31名年龄匹配的健康供者。从所有参与者中分离外周血单核细胞（PBMCs）。收集10份宫颈活检组织用于TIL（肿瘤浸润淋巴细胞）分离和石蜡固定。通过多参数流式细胞术和免疫组织化学分析免疫检查点表达。 结果：在外周血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TIL（肿瘤浸润淋巴细胞）中，这些相同分子以及NKG2A进一步显著上调。虽然BTLA和NKG2A未显示全身性变化，但NKG2A在TIL中升高，BTLA在TIL中降低。与患者PBMCs相比，TIL中PD-1与TIGIT、Tim-3、LAG-3和NKG2A的共表达显著富集2至6倍。肿瘤微环境具有高度免疫抑制性，其特征是PD-1、PD-L1和TIGIT富集；与早期肿瘤相比，TIGIT在局部晚期肿瘤中显著上调。 结论：我们的研究结果突出了初治患者宫颈肿瘤的强免疫抑制环境，以及治疗前和治疗后患者外周血中抑制性检查点表达升高。这些结果强调了研究肿瘤部位本身免疫调节的重要性，并提示免疫检查点共表达可能作为T细胞耗竭和治疗耐药的生物标志物。理解治疗如何改变这些通路，可能有助于指导合理的联合免疫治疗，以恢复宫颈癌中CD8 + T细胞功能。
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-na ve 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-na ve 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.
MEMBER ACCOUNT
登录成功会直接打开下一页。
