Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients.
Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients.
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DOI：
10.1038/nm.4051
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发表时间：
2016-04
期刊：
影响因子：
82.9
通讯作者：
Rosenberg SA
中科院分区：
文献类型：
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作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
针对肿瘤特异性突变新抗原(源自肿瘤中突变基因编码的产物)的淋巴细胞的检测大多限于肿瘤常驻淋巴细胞，但这些淋巴细胞是否经常出现在循环中尚不清楚。我们最近报道，程序性细胞死亡1(PD-1)受体在肿瘤内的表达可以指导识别肿瘤中的肿瘤反应性CD8+淋巴细胞。鉴于这些发现，我们调查了外周血淋巴细胞上PD-1的表达是否可以作为检测针对新抗原的T细胞的生物标志物。通过使用高通量的个性化筛选方法，我们在四名黑色素瘤患者中的三名患者的外周血中鉴定出了新抗原特异性淋巴细胞。尽管它们在循环中的频率很低，但我们发现CD8+PD-1+，而不是CD8+PD-1−，细胞群体中有针对3，3和1个独特的患者特异性新抗原的淋巴细胞。我们发现，从外周血中分离出来的新抗原特异性T细胞和表达新抗原特异性T细胞受体(TCR)的基因工程淋巴细胞可以识别自体肿瘤。值得注意的是，循环CD8+PD-1+细胞和肿瘤浸润性CD8+PD-1+细胞的肿瘤抗原特异性和TCR谱相似，这意味着循环CD8+PD-1+淋巴细胞可以为肿瘤驻留的抗肿瘤淋巴细胞提供一个窗口。因此，PD-1的表达识别了外周血中多样化和患者特异性的抗肿瘤T细胞反应，为利用新抗原反应性淋巴细胞或TCR治疗癌症提供了一种新的非侵入性策略。
Detection of lymphocytes that target tumor-specific mutant neoantigens—derived from products encoded by mutated genes in the tumor—is mostly limited to tumor-resident lymphocytes, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8+ lymphocytes that reside in the tumor. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8+PD-1+, but not CD8+PD-1−, cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8+PD-1+ cells appeared similar, implying that the circulating CD8+PD-1+ lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.
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DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
15.9
作者：
Cohen, Cyrille J.;Gartner, Jared J.;Robbins, Paul F.
通讯作者：
Robbins, Paul F.
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
4.4
作者：
Haga-Friedman, Astar;Horovitz-Fried, Miryam;Cohen, Cyrille J.
通讯作者：
Cohen, Cyrille J.
影响因子：
56.9
作者：
Altman, JD;Moss, PAH;Davis, MM
通讯作者：
Davis, MM