Progressive Upregulation of PD-1 in Primary and Metastatic Melanomas Associated with Blunted TCR Signaling in Infiltrating T Lymphocytes
Progressive Upregulation of PD-1 in Primary and Metastatic Melanomas Associated with Blunted TCR Signaling in Infiltrating T Lymphocytes
复制标题
DOI：
10.1038/jid.2011.30
复制
发表时间：
2011-06-01
影响因子：
6.5
通讯作者：
Bercovici, Nadege
中科院分区：
文献类型：
--
作者：
Chapon, Maxime;Randriamampita, Clotilde;Bercovici, Nadege
程序性死亡-1（PD-1）参与T细胞对自身抗原的耐受。对于一些癌症，已经表明PD-1的配体（即PD-L1）的表达可能有助于肿瘤逃避免疫破坏。然而，肿瘤浸润性T淋巴细胞（TIL）上的PD-1表达、疾病分期和TIL反应性之间的关系仍缺乏文献记载。在这项研究中，我们发现新鲜分离的CD 4（+）和CD 8（+）TIL在原发性黑色素瘤中表达大量的PD-1。PD-1的表达在远处皮肤转移的晚期进一步增加，尤其是在CD 8（+）TIL上。PD-1配体的表达仅在肿瘤细胞和肿瘤源性骨髓细胞上的转移中频繁。从这些皮肤肿瘤分离的TIL离体反应性差，在TCR刺激后具有钝化的钙应答和IFN-γ产生。令人惊讶的是，在原发性黑色素瘤的不同部位，无论是侵袭性的还是消退的，我们发现TILs类似地表达PD-1并保持功能障碍。PD-1和PD-L1在转移性黑色素瘤病变中的表达可以被认为是不成功的抗肿瘤免疫应答的见证，但PD-1在疾病严重程度中的直接参与以及TIL在肿瘤消退中的重要性仍有待确定。
Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-gamma production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.