Le Gal Frédérique-Anne, Widmer Valérie M, Dutoit Valérie, Rubio-Godoy Verena, Schrenzel Jacques, Walker Paul R, Romero Pedro J, Valmori Danila, Speiser Daniel E, Dietrich Pierre-Yves
Laboratory of Tumor Immunology, Division of Oncology, Department of Internal Medicine, University Hospital, Geneva, Switzerland.
J Invest Dermatol. 2007 Mar;127(3):622-9. doi: 10.1038/sj.jid.5700580. Epub 2006 Oct 12.
Tumor antigen-specific cytotoxic T cells (CTLs) play a major role in the adaptive immune response to cancers. This CTL response is often insufficient because of functional impairment, tumor escape mechanisms, or inhibitory tumor microenvironment. However, little is known about the fate of given tumor-specific CTL clones in cancer patients. Studies in patients with favorable outcomes may be very informative. In this longitudinal study, we tracked, quantified, and characterized functionally defined antigen-specific T-cell clones ex vivo, in peripheral blood and at tumor sites, in two long-term melanoma survivors. MAGE-A10-specific CD8+ T-cell clones with high avidity to antigenic peptide and tumor lytic capabilities persisted in peripheral blood over more than 10 years, with quantitative variations correlating with the clinical course. These clones were also found in emerging metastases, and, in one patient, circulating clonal T cells displayed a fully differentiated effector phenotype at the time of relapse. Longevity, tumor homing, differentiation phenotype, and quantitative adaptation to the disease phases suggest the contribution of the tracked tumor-reactive clones in the tumor control of these long-term metastatic survivor patients. Focusing research on patients with favorable outcomes may help to identify parameters that are crucial for an efficient antitumor response and to optimize cancer immunotherapy.
肿瘤抗原特异性细胞毒性T细胞（CTLs）在针对癌症的适应性免疫反应中起主要作用。由于功能受损、肿瘤逃逸机制或抑制性肿瘤微环境，这种CTL反应往往不足。然而，对于癌症患者中特定肿瘤特异性CTL克隆的命运知之甚少。对预后良好的患者进行的研究可能会提供很多信息。在这项纵向研究中，我们在两名长期存活的黑色素瘤患者的外周血和肿瘤部位，对功能明确的抗原特异性T细胞克隆进行了体外追踪、定量和表征。对抗原肽具有高亲和力且具有肿瘤溶解能力的MAGE - A10特异性CD8 + T细胞克隆在外周血中持续存在超过10年，其数量变化与临床病程相关。这些克隆也在新出现的转移灶中被发现，并且在一名患者中，循环克隆T细胞在复发时表现出完全分化的效应细胞表型。克隆的长寿、肿瘤归巢、分化表型以及对疾病阶段的定量适应表明，所追踪的肿瘤反应性克隆在这些长期转移性存活患者的肿瘤控制中发挥了作用。将研究重点放在预后良好的患者身上可能有助于确定有效抗肿瘤反应的关键参数，并优化癌症免疫治疗。
