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Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding αPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-γ production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-γ/TNF-α double-producing CD8+ T cells within the tumor. These results suggest that combination blockade of the PD-1/ PD-L1- and CTLA-4-negative costimulatory pathways allows tumorspecific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory |
版主 (文壇精英)
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接種照射過的B16黑色素瘤細(xì)胞表達(dá)GM-CSF(GVAX)配體或FLT3-配體(Fvax)結(jié)合負(fù)反饋T細(xì)胞共刺激受體細(xì)胞毒性的T淋巴細(xì)胞抗原4(CTLA-4)的抗體阻斷功能促進(jìn)排斥預(yù)先植入腫瘤。盡管由于CTLA-4的阻斷作用,T-細(xì)胞的增殖和細(xì)胞因子的產(chǎn)生可通過程序性死亡-1(PD-1)與它的配體PD-L1和PD-L2或由PD-L1的與B7-1的相互作受到抑制。然而,我們研究表明,CTLA-4和PD-1阻斷結(jié)合對B16黑色素瘤細(xì)胞的排斥效率是CTLA-4與Fvax結(jié)合或PD-1與Fvax結(jié)合兩倍以上。添加αPD-L1到CTLA-4,結(jié)果65%的預(yù)先植入腫瘤被排斥,不加αPD-L1而單靠CTLA-4阻斷則僅有10%的預(yù)先植入腫瘤被排斥 。PD-1和CTLA-4阻斷結(jié)合增加了效應(yīng)T細(xì)胞(Teff)浸潤,導(dǎo)致極有利的效應(yīng)T 細(xì)胞轉(zhuǎn)變?yōu)獒槍δ[瘤的調(diào)節(jié)性T細(xì)胞的比例。浸潤到腫瘤部分的效應(yīng)T細(xì)胞的CTLA-4和PD-1表達(dá)增加,這反映了細(xì)胞增殖和細(xì)胞積累增加,否則細(xì)胞將失活。聯(lián)合阻斷作用協(xié)同增加B16黑色素瘤中效應(yīng)T細(xì)胞轉(zhuǎn)化為髓源抑制細(xì)胞的比例。在腫瘤和疫苗接種后的淋巴結(jié)引流IFN-γ的產(chǎn)量均增加,IFN-γ/TNF-α在腫瘤內(nèi)翻倍產(chǎn)生CD8 + T細(xì)胞的比率也增加了。這些結(jié)果表明,PD-1 /PD-L1-和CTLA-4負(fù)反饋共刺激途徑的聯(lián)合阻斷使腫瘤特異性T細(xì)胞,本來要被滅活的,繼續(xù)擴(kuò)展和發(fā)揮效應(yīng)功能,從而將腫瘤微環(huán)境從抑制狀態(tài)改變?yōu)檠装Y狀態(tài)。 GM-CSF (Gvax)------Granulocyte-Macrophage Colony-Stimulating Factor (Colony Stimulating Factor 2):粒細(xì)胞 - 巨噬細(xì)胞集落刺激因子(細(xì)胞集落刺激因子2) |

禁蟲 (正式寫手)
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木蟲 (小有名氣)
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接種過疫苗的被輻射的B16黑色素瘤細(xì)胞,或者表達(dá) 粒細(xì)胞巨噬細(xì)胞刺激因子,或者表達(dá)髓系細(xì)胞觸發(fā)受體-Flt3,通過二者之一(Gvax或Fvax)與抗體的結(jié)合,來阻滯陰性T細(xì)胞共刺激受體-細(xì)胞毒性T細(xì)胞抗原4來增強(qiáng)預(yù)先植入腫瘤的排斥反應(yīng)。盡管細(xì)胞毒性T細(xì)胞抗原4通路被阻滯了,T細(xì)胞的增殖及細(xì)胞因子的分泌可以被程序性死亡因子1及其配體PD-L1 和PD-L2的相互作用抑制,或者被 PD-L1 和 B7-1的相互作用抑制。在這里,我們展示了CTLA-4 和 PD-1結(jié)合的阻滯作用要比二者任一在增強(qiáng)B16黑色素瘤細(xì)胞與Fvax的結(jié)合產(chǎn)生排斥反應(yīng)的效果高兩倍還多。在療程中加入αPD-L1導(dǎo)致65% 預(yù)先植入腫瘤的排斥反應(yīng),而相對應(yīng)的是10%的CTLA-4 阻滯。PD-1 和 CTLA-4 的聯(lián)合阻滯加強(qiáng)了效應(yīng)T細(xì)胞的浸潤,這有利于提高調(diào)節(jié)性T細(xì)胞與腫瘤的結(jié)合速率。腫瘤浸潤部位T細(xì)胞的CTLA-4 和 PD-1表達(dá)量增加,反映在細(xì)胞被其他因素刺激而導(dǎo)致增殖及數(shù)量增加。在B16黑色素瘤中,聯(lián)合阻滯也通過協(xié)同作用增加髓源性抑T細(xì)胞的增殖速率。 IFN-γ在腫瘤及疫苗引流淋巴結(jié)中分泌量都有所增加,是在腫瘤中的CD8+ T 細(xì)胞分泌的 IFN-γ/TNF-α的兩倍。這些結(jié)果表明:PD-1 和 CTLA-4 的聯(lián)合阻滯共刺激通路允許被其他因素抑制的特異性T細(xì)胞繼續(xù)擴(kuò)增并產(chǎn)生效應(yīng)作用,因此改變腫瘤區(qū)微環(huán)境由抑制態(tài)向炎性態(tài)轉(zhuǎn)變。 拙見,供參考,有些專業(yè)詞匯翻譯的可能不太到位 |
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