CD91及其配体gp96在新生、出现性肿瘤免疫应答中赋予多种APC交叉激活能力

CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors

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Cancer Immunology Research

影响因子:8.2

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

DOI: 10.1158/2326-6066.CIR-24-0326

摘要

在癌症免疫监视过程中，树突状细胞（DC）在协调针对新兴肿瘤的T细胞反应中起核心作用。捕获极少量的抗原及肿瘤引发的共刺激信号，可以驱动DC的成熟。DC上的CD91表达在新生肿瘤背景下的T细胞交叉激活中至关重要。多种DC和巨噬细胞亚群表达CD91，并通过与肿瘤来源的gp96结合，启动抗肿瘤免疫反应，但在癌症免疫监视中，具体负责T细胞交叉激活的CD91+抗原呈递细胞（APC）尚不明确。本研究确定，CD91在1型常规DC（cDC1）上的表达对于癌症免疫监视是必需的。具体而言，表达CD91的cDC1能从肿瘤中捕获CD91配体gp96，迁移到淋巴结后，将gp96分配给淋巴结内的APC。然而，捕获肿瘤来源gp96的cDC1仅能提供早期肿瘤控制，而持续和长期的肿瘤排斥则由其他表达gp96的交叉激活DC实现。我们还发现，APC中由CD91诱导的转录组促进T细胞反应的交叉激活，同时抑制免疫调节途径。我们的结果显示，APC在通过CD91成功清除癌细胞的过程中，表现出复杂且同步的分工。我们预测，APC亚群的专门功能可被利用于疾病的免疫治疗。

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.