Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cell. 2024 Jul 25;187(15):3888-3903.e18. doi: 10.1016/j.cell.2024.05.026. Epub 2024 Jun 12.
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 unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8 T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4 T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4 T cells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.
晚年宿主防御功能缺陷与免疫细胞活性变化有关，这表明免疫疗法方法需要考虑特定年龄因素。在这项研究中，我们发现基于 PD-1 和 CTLA4 的癌症免疫疗法无法根除老年小鼠的肿瘤。这种抗肿瘤活性的缺陷与两个已知的与年龄相关的免疫缺陷有关：系统幼稚 CD8 T 细胞的丰度降低和树突状细胞（DC）的迁移活性减弱。我们鉴定了一种疫苗佐剂，称为 DC 激活剂，它可以纠正老年个体中 DC 的迁移缺陷。含有肿瘤抗原和 DC 激活剂的疫苗诱导具有细胞毒性活性的辅助性 T 细胞 1（TH1）CD4 T 细胞，从而在老年小鼠中驱动抗肿瘤免疫。当在生命早期给药时，DC 激活剂是唯一被鉴定出的佐剂，可引发持续存在于老年期的抗肿瘤 CD4 T 细胞。这些结果提出了通过 DC 操作纠正与年龄相关的免疫缺陷的可能性。
