在免疫反应期间，CD91及其配体GP96赋予多个APC的交叉染色功能
CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors
影响因子:8.20000
分区:医学1区 Top / 免疫学2区 肿瘤学2区
发表日期:2024 Dec 03
作者:
Devanshi A Nayak, Abigail L Sedlacek, Anthony R Cillo, Simon C Watkins, Robert J Binder
摘要
在癌症免疫监测期间，树突状细胞（DC）在策划针对新兴肿瘤的T细胞反应中起着核心作用。捕获微小量的抗原以及肿瘤引发的共刺激信号可以推动DC的成熟。在新生肿瘤的背景下，CD91在DCS上的表达对于T细胞响应的交叉染色至关重要。多个DC和巨噬细胞亚群表达CD91并参与肿瘤衍生的GP96以启动抗肿瘤免疫反应，但是在癌症免疫保留期间T细胞交叉宣传所需的特定CD91+抗原呈递细胞（APC）尚不清楚。在这项研究中，我们确定在1型常规DC（CDC1）上的CD91表达对于癌症免疫监视是必需的。具体而言，发现表达CD91的CDC1可以从肿瘤中捕获CD91配体GP96，并且在迁移到淋巴结后，在淋巴结驻留的APC中分布GP96。但是，捕获肿瘤衍生的GP96的CDC1仅提供早期肿瘤控制，而持续和长期的肿瘤排斥反应则由其他GP96+交叉宣传DC授予宿主。我们进一步发现，CD91诱导的APC中的转录组促进了T细胞反应的交叉宣传，同时下调免疫调节途径。我们的结果表明，通过CD91成功消除癌细胞，APC的劳动劳动分裂详细且同步。我们预测，可以利用APC子集的专门功能来进行疾病的免疫疗法。
Abstract
During cancer immunosurveillance, dendritic cells (DC) play a central role in orchestrating T-cell responses against emerging tumors. Capture of miniscule amounts of antigen along with tumor-initiated costimulatory signals can drive maturation of DCs. Expression of CD91 on DCs is essential in cross-priming of T-cell responses in the context of nascent tumors. Multiple DC and macrophage subsets express CD91 and engage tumor-derived gp96 to initiate antitumor immune responses, yet the specific CD91+ antigen-presenting cells (APC) that are required for T-cell cross-priming during cancer immunosurveillance are unknown. In this study, we determined that CD91 expression on type 1 conventional DCs (cDC1) is necessary for cancer immunosurveillance. Specifically, CD91-expressing cDC1 were found to capture the CD91 ligand gp96 from tumors and, upon migration to the lymph nodes, distribute gp96 among lymph node-resident APCs. However, cDC1 that captured tumor-derived gp96 only provided early tumor control, whereas sustained and long-term tumor rejection was bestowed to the host by other gp96+ cross-priming DCs. We further found that the CD91-induced transcriptome in APCs promoted cross-priming of T-cell responses while downregulating immune regulatory pathways. Our results show an elaborate and synchronized division of labor of APCs in the successful elimination of cancer cells via CD91. We predict that the specialized functions of APC subsets can be harnessed for immunotherapy of disease.