邻近依赖标记识别驱动肿瘤特异性CD4+ T细胞反应的树突状细胞

Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response

Science Immunology

影响因子:16.3

分区:医学1区 Top / 免疫学1区

发表日期:2024 Oct 04

作者: Aleksey Chudnovskiy, Tiago B R Castro, Sandra Nakandakari-Higa, Ang Cui, Chia-Hao Lin, Moshe Sade-Feldman, Brooke K Phillips, Juhee Pae, Luka Mesin, Juliana Bortolatto, Lawrence D Schweitzer, Giulia Pasqual, Li-Fan Lu, Nir Hacohen, Gabriel D Victora

DOI: 10.1126/sciimmunol.adq8843

摘要

树突状细胞（DC）具有独特能力，能将肿瘤抗原转运至肿瘤引流淋巴结（tdLNs），并在肿瘤微环境（TME）中与效应T细胞相互作用，介导自然抗肿瘤免疫和免疫检查点阻断治疗反应。利用基于LIPSTIC（用Sor标签标记细胞间接触的免疫伙伴关系）技术的单细胞转录组学，我们识别出能够在tdLN和TME中呈递抗原给CD4+ T细胞的单个DCs。研究发现，具有相似高激活转录表型的DC在肿瘤及tdLN中与辅助T细胞相互作用，这些相互作用在免疫检查点阻断药物的作用下增强。结果表明，少量DCs负责在tdLN和TME中大部分抗原的呈递，且传统的免疫检查点阻断药物能增强在两个部位的CD40驱动的DC激活。

Abstract

Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4+ T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.