Dysregulated NF-κB-Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma.
Dysregulated NF-κB-Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma.
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DOI：
10.1158/2326-6066.cir-20-0274
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发表时间：
2020-12
影响因子：
10.1
通讯作者：
Butterfield LH
中科院分区：
文献类型：
--
作者：
Maurer DM;Adamik J;Santos PM;Shi J;Shurin MR;Kirkwood JM;Storkus WJ;Butterfield LH
针对黑色素瘤相关抗原的治疗性癌症疫苗通常是免疫原性的，但很少能有效地促进客观的临床反应。为了确定激活有效抗肿瘤免疫的关键分子，我们已经设计了用于治疗35例黑色素瘤患者的自体树突状细胞(DC)疫苗。我们发现，体外成熟诱导的检查点分子与体内DC疫苗活性相关。黑色素瘤患者树突状细胞表面ICOSL表达减少，固有的核因子-kB信号缺陷。芯片分析显示，DC对ICOSL表达的转录调控依赖于核因子-kB。ICOSL对DC的阻断在体外减少了来自幼稚捐赠者的抗原特异性CD8+和CD4+T细胞的启动。从疫苗树突状细胞释放的细胞外/可溶性ICOSL浓度与患者的临床结果呈正相关，我们发现这部分受ADAM10/17脱落酶活性的调节。这些数据指出了典型的核因子-kB信号、基质金属蛋白酶的调节以及DC来源的ICOSL在癌症背景下同源T细胞反应的特异性启动中的关键作用。这项研究支持实施有针对性的策略，以增强这些途径，以改善癌症患者的免疫治疗结果。
Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic, but are rarely effective in promoting objective clinical responses. To identify critical molecules for activation of effective antitumor immunity, we have profiled autologous dendritic cell (DC) vaccines used to treat 35 patients with melanoma. We showed that checkpoint molecules induced by ex vivo maturation correlated with in vivo DC vaccine activity. melanoma patient DCs had reduced expression of cell surface ICOSL and had defective intrinsic NF-kB signaling. ChIP assays revealed NF-kB-dependent transcriptional regulation of ICOSL expression by DCs. Blockade of ICOSL on DCs reduced priming of antigen-specific CD8+ and CD4+ T cells from naïve donors in vitro. Concentration of extracellular/soluble ICOSL released from vaccine DCs positively correlated with patient clinical outcomes, which we showed to be partially regulated by ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-kB signaling, the regulation of matrix metalloproteinases, and DC-derived ICOSL in the specific priming of cognate T-cell responses in the cancer setting. This study supports the implementation of targeted strategies to augment these pathways for improved immunotherapeutic outcomes in cancer patients.