Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.
Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.
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DOI：
10.1158/0008-5472.can-12-4100
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发表时间：
2013-06-15
期刊：
影响因子：
11.2
通讯作者：
Coukos G
中科院分区：
文献类型：
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作者：
Duraiswamy J;Kaluza KM;Freeman GJ;Coukos G
调节性T细胞(Tregs)促进肿瘤进展，而效应性T细胞则限制肿瘤进展。在这项研究中，我们记录了程序性死亡-1(PD-1，PDCD1)对CD8+T细胞和Foxp3+Tregs的平行调节。此外，在肿瘤模型(CT26结肠癌和ID8-VEGF卵巢癌)中，我们还发现了细胞毒性T淋巴细胞抗原-4(CTLA-4)抑制受体在进一步促进CD8+T效应细胞功能障碍方面的作用。2/3的CD8+肿瘤浸润性淋巴细胞(TIL)表达PD-1，1/3~一半的CD8+TIL共表达PD-1和CTLA-4。双阳性(PD-1+CTLA-4+)CD8+TIL较单阳性(PD-1+或CTLA-4+)TIL具有更严重的功能障碍，包括不能增殖和分泌效应细胞因子。阻断PD-1和CTLA-4均可逆转CD8+TIL功能障碍，并导致三分之二的小鼠肿瘤排斥反应。双重阻断与抗原特异性效应物CD8+和CD4+T细胞的增殖增加、抗原特异性细胞因子的释放、Tregs抑制功能的抑制以及对T细胞功能至关重要的关键信号分子上调有关。当与GVAX疫苗(由GM-CSF照射的肿瘤细胞组成)联合使用时，抑制通路阻断对CT26肿瘤的排斥反应百分率为100%，对ID8-VEGF肿瘤的排斥反应为75%。我们的研究表明，肿瘤中的PD-1信号是抑制效应性T细胞和维持肿瘤Tregs所必需的，而PD-1/PD-L1通路(CD274)阻断通过增加效应性T细胞的活性来增强对肿瘤的抑制，同时减弱Treg细胞的抑制。
Tumor progression is facilitated by regulatory T cells (Tregs) and restricted by effector T cells. In this study, we document parallel regulation of CD8+ T cells and Foxp3+ Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8+ T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8+ tumor-infiltrating lymphocytes (TIL) expressed PD-1, while one third to half of CD8+ TIL co-expressed PD-1 and CTLA-4. Double-positive (PD-1+CTLA-4+) CD8+ TIL had characteristics of more severe dysfunction than single-positive (PD-1+ or CTLA-4+) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in two-thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T cell function. When used in combination with GVAX vaccination (consisting of GM-CSF-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T cell activity, while attenuating Treg cell suppression.