PO.IM02.04 · 免疫学
衰老使B细胞成为削弱肿瘤防御的CD8⁺细胞的驱动因素
Aging turns B cells into drivers of CD8⁺ cells that weaken tumor defenses
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
尽管衰老是癌症的主要风险因素，但年龄诱导的免疫失调对肿瘤控制的影响仍知之甚少。虽然CD8⁺ T细胞是抗肿瘤免疫的核心，但衰老会改变其表型及其与其他免疫细胞的相互作用。我们利用多参数流式细胞术、功能检测、单细胞RNA测序和ATAC-seq，鉴定出一个在表型和表观遗传上独特的CD8⁺ T细胞群体（DP8），该群体随年龄增长在小鼠中积累，可能也在老年人中积累。DP8细胞表现出非耗竭的CD101⁺CXCR6⁺CD39⁺CD73⁺表型。从机制上讲，DP8的分化由衰老的B细胞驱动，因为衰老的（而非年轻的）B细胞可诱导DP8身份，且B细胞缺陷可阻止其出现。在功能上，DP8细胞抑制CD4⁺ T细胞活化并促进肿瘤进展，表达CXCL16的肿瘤选择性地将DP8细胞招募到肿瘤微环境中，在那里它们损害抗肿瘤免疫。我们提出DP8细胞是有吸引力的治疗靶点，因为DP8样细胞似乎在老年人中也增加，包括在晚发性乳腺癌中。在衰老小鼠中，即使anti-PD1治疗失败，清除DP8细胞或其诱导者B细胞也能有效逆转肿瘤生长。
查看英文原文 English abstract
Despite aging being a major risk factor for cancer, the effect of age-induced immune dysregulation in tumor control is poorly understood. While CD8⁺ T cells are central to antitumor immunity, aging changes their phenotype and interactions with other immune cells. Using multiparameter flow cytometry, functional assays. single-cell RNA sequencing, and ATAC-seq, we identify a phenotypically and epigenetically distinct CD8⁺ T cell population (DP8) that accumulates with age in mice and possibly in older humans. DP8 cells exhibit a non-exhausted CD101⁺CXCR6⁺CD39⁺CD73⁺ phenotype. Mechanistically, DP8 differentiation is driven by aging B cells, as aged-but not young-B cells induce DP8 identity and B cell deficiency prevents their emergence. Functionally, DP8 cells suppress CD4⁺ T cell activation and promote tumor progression, and tumors expressing CXCL16 selectively recruit DP8 cells into the tumor microenvironment where they impair antitumor immunity. We propose that DP8 cells are attractive therapeutic targets, as DP8-like cells appear to also increase in older humans, including in late onset breast cancer. In aged mice, the depletion of DP8 cells or their inducer B cells efficiently reverses tumor growth even when anti-PD1 therapy fails.
利益披露 Disclosure
M. Bodogai, None..
B. Park, None..
F. Braikia, None..
K. Konda, None..
A. Biragyn, None.