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Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors
Cell ( IF 45.5 ) Pub Date : 2024-06-12 , DOI: 10.1016/j.cell.2024.05.026 Dania Zhivaki 1 , Stephanie N Kennedy 1 , Josh Park 2 , Francesco Boriello 3 , Pascal Devant 1 , Anh Cao 1 , Kristin M Bahleda 1 , Shane Murphy 2 , Cristin McCabe 2 , Charles L Evavold 1 , Kate L Chapman 1 , Ivan Zanoni 3 , Orr Ashenberg 2 , Ramnik J Xavier 2 , Jonathan C Kagan 1
Cell ( IF 45.5 ) Pub Date : 2024-06-12 , DOI: 10.1016/j.cell.2024.05.026 Dania Zhivaki 1 , Stephanie N Kennedy 1 , Josh Park 2 , Francesco Boriello 3 , Pascal Devant 1 , Anh Cao 1 , Kristin M Bahleda 1 , Shane Murphy 2 , Cristin McCabe 2 , Charles L Evavold 1 , Kate L Chapman 1 , Ivan Zanoni 3 , Orr Ashenberg 2 , Ramnik J Xavier 2 , Jonathan C Kagan 1
Affiliation
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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.
中文翻译：
纠正树突状细胞中与年龄相关的缺陷使 CD4+ T 细胞能够根除肿瘤
晚年宿主防御缺陷与免疫细胞活性的变化有关，这表明免疫治疗方法需要考虑年龄特异性。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。这种抗肿瘤活性缺陷与两种已知的与年龄相关的免疫缺陷相关：全身幼稚 CD8 T 细胞丰度减少和树突状细胞 (DC) 迁移活性弱。我们发现了一种称为 DC 过度激活剂的疫苗佐剂，它可以纠正老年人的 DC 迁移缺陷。含有肿瘤抗原和 DC 过度激活剂的疫苗可诱导具有细胞溶解活性的 1 型辅助 T (TH1) CD4 T 细胞，从而驱动老年小鼠的抗肿瘤免疫。在生命早期施用时，DC 过度激活剂是唯一被鉴定出能够引发持续到老年的抗肿瘤 CD4 T 细胞的佐剂。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。
更新日期：2024-06-12
中文翻译：
纠正树突状细胞中与年龄相关的缺陷使 CD4+ T 细胞能够根除肿瘤
晚年宿主防御缺陷与免疫细胞活性的变化有关，这表明免疫治疗方法需要考虑年龄特异性。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。这种抗肿瘤活性缺陷与两种已知的与年龄相关的免疫缺陷相关：全身幼稚 CD8 T 细胞丰度减少和树突状细胞 (DC) 迁移活性弱。我们发现了一种称为 DC 过度激活剂的疫苗佐剂，它可以纠正老年人的 DC 迁移缺陷。含有肿瘤抗原和 DC 过度激活剂的疫苗可诱导具有细胞溶解活性的 1 型辅助 T (TH1) CD4 T 细胞，从而驱动老年小鼠的抗肿瘤免疫。在生命早期施用时，DC 过度激活剂是唯一被鉴定出能够引发持续到老年的抗肿瘤 CD4 T 细胞的佐剂。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。
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