美国波士顿儿童医院Jonathan C. Kagan研究团队发现，纠正树突状细胞与年龄有关的缺陷可使CD4+ T细胞消灭肿瘤。相关论文于2024年6月12日在线发表在《细胞》杂志上。

研究人员发现基于PD-1和CTLA4的癌症免疫疗法无法根除老年小鼠的肿瘤。这种抗肿瘤活性缺陷与两个已知的年龄相关免疫缺陷有关：系统性初始CD8⁺ T细胞数量减少和树突状细胞（DC）迁移活动减弱。

研究人员发现了一种疫苗佐剂，称为DC超激活剂，它能纠正老年DC迁移缺陷。含有肿瘤抗原和DC超激活剂的疫苗能诱导具有细胞溶解活性的T辅助1型（TH1）CD4⁺ T细胞，从而增强老年小鼠的抗肿瘤免疫力。

在生命早期给药时，DC超激活剂是唯一能诱导抗肿瘤CD4⁺ T细胞并持续到老年的佐剂。这些结果为通过操纵DC纠正与年龄相关的免疫缺陷提供了可能性。

据悉，老年宿主防御功能的缺陷与免疫细胞活性的变化有关，这表明在采用免疫疗法时需要考虑年龄特异性。

附：英文原文

Title: Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors

Author: Dania Zhivaki, Stephanie N. Kennedy, Josh Park, Francesco Boriello, Pascal Devant, Anh Cao, Kristin M. Bahleda, Shane Murphy, Cristin McCabe, Charles L. Evavold, Kate L. Chapman, Ivan Zanoni, Orr Ashenberg, Ramnik J. Xavier, Jonathan C. Kagan

Issue&Volume: 2024-06-12

Abstract: Defective host defenses later in life are associated with changes in immune cell activities,suggesting that age-specific considerations are needed in immunotherapy approaches.In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unableto eradicate tumors in elderly mice. This defect in anti-tumor activity correlatedwith two known age-associated immune defects: diminished abundance of systemic naiveCD8+ T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccineadjuvant, referred to as a DC hyperactivator, which corrects DC migratory defectsin the elderly. Vaccines containing tumor antigens and DC hyperactivators inducedT helper type 1 (TH1) CD4+ T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. Whenadministered early in life, DC hyperactivators were the only adjuvant identified thatelicited anti-tumor CD4+ T cells that persisted into old age. These results raise the possibility of correctingage-associated immune defects through DC manipulation.

DOI: 10.1016/j.cell.2024.05.026

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00535-X