PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines.
PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines.
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DOI：
10.1158/0008-5472.can-13-2908
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Zarour HM
中科院分区：
文献类型：
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作者：
Fourcade J;Sun Z;Pagliano O;Chauvin JM;Sander C;Janjic B;Tarhini AA;Tawbi HA;Kirkwood JM;Moschos S;Wang H;Guillaume P;Luescher IF;Krieg A;Anderson AC;Kuchroo VK;Zarour HM
虽然黑色素瘤疫苗刺激肿瘤抗原（TA）特异性CD 8 + T细胞，但很少观察到客观的临床反应。为了研究这种差异，我们评估了在施用肿瘤疫苗的转移性黑色素瘤患者中疫苗诱导的CD 8 + T细胞关于抑制性T细胞共受体PD-1和Tim-3的特征。疫苗包括不完全弗氏佐剂（IFA）、CpG寡脱氧核苷酸（CpG）和HLA-A2限制性类似物肽NY-ESO-1157 - 165 V，单独或与泛DR表位NY-ESO-1119 -143组合。两种疫苗均刺激离体检测到的快速TA特异性CD 8 + T细胞应答，然而，TA特异性CD 8 + T细胞在用MHC I类和II类表位免疫后产生更多的IFN-γ并表现出更高的裂解功能。值得注意的是，绝大多数疫苗诱导的CD 8 + T细胞上调PD-1，少数也上调Tim-3。在疫苗给药时，疫苗诱导的CD 8 + T细胞的PD-1和Tim-3表达水平与其体内扩增呈负相关。PD-1和Tim-3的双重阻断增强了疫苗诱导的CD 8 + T细胞的体外扩增和细胞因子产生。总的来说，我们的研究结果支持使用PD-1和Tim-3阻断剂与癌症疫苗一起刺激有效的抗肿瘤T细胞应答，并增加晚期黑色素瘤患者临床应答的可能性。
Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8+ T cells with regard to the inhibitory T cell co-receptors PD-1 and Tim-3 in metastatic melanoma patients who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant (IFA), CpG oligodeoxynucleotide (CpG) and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T-cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in advanced melanoma patients.