Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer
Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer
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DOI：
10.1073/pnas.1003345107
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发表时间：
2010-04-27
影响因子：
11.1
通讯作者：
Odunsi, Kunle
中科院分区：
文献类型：
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作者：
Matsuzaki, Junko;Gnjatic, Sacha;Odunsi, Kunle
NY-ESO-1 是一种经常在上皮性卵巢癌 (EOC) 中表达的“癌睾丸”抗原，并且是迄今为止定义的最具免疫原性的肿瘤抗原之一。为了了解体内耐受机制，我们评估了来自表达NY-ESO-1肿瘤的EOC患者的外周血淋巴细胞（PBL）、肿瘤浸润淋巴细胞（TIL）和肿瘤相关淋巴细胞（TAL）的NY-ESO-1特异性CD8（+）T细胞的表型和功能，无论其有或没有对NY-ESO-1的体液免疫。虽然NY-ESO-1特异性CD8(+) T细胞在血清阳性患者的TIL和TAL中很容易在体外用四聚体检测到，但它们只能在体外刺激后在PBL中检测到。与PBL相比，肿瘤源性NY-ESO-1特异性CD8+T细胞表现出效应功能受损、优先使用优势T细胞受体以及抑制分子LAG-3和PD-1共表达丰富。 IL-10、IL-6（肿瘤腹水中发现的细胞因子）和肿瘤源性抗原呈递细胞上调 CD8+ T 细胞上 LAG-3 和 PD-1 的表达。在功能上，与 LAG-3(+)PD-1(-) 或 LAG-3(-)PD-1(-) 亚群相比，CD8(+)LAG-3(+)PD-1(+) T 细胞在 IFN-γ/TNF-α 产生方面受到更多损害。 T细胞启动过程中LAG-3和PD-1的双重阻断有效地增强了NY-ESO-1特异性CD8+T细胞的增殖和细胞因子产生，表明NY-ESO-1特异性CD8+T细胞的抗肿瘤功能可能通过这些抑制性受体的治疗靶向得到改善。
NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.