Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors

被引：1

作者：

Kadyrzhanova, Gulfiya ^{[1
]}

Tamai, Miho ^{[1
]}

Sarkar, Shukla ^{[1
]}

Kalra, Rajkumar Singh ^{[1
]}

Ishikawa, Hiroki ^{[1
]}

机构：

[1] Grad Univ OIST, Okinawa Inst Sci & Technol, Immune Signal Unit, Onna, Okinawa, Japan

来源：

FRONTIERS IN IMMUNOLOGY | 2025年 / 16卷

关键词：

aging; adoptive T-cell therapy; cancer; CD8 T cells; Epas1; ANTITUMOR IMMUNITY; AGE; ACTIVATION; SUSCEPTIBILITY; TRANSCRIPTION; METABOLISM; EXPRESSION; GENERATION; INCREASE; DECLINE;

D O I：

10.3389/fimmu.2025.1484303

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Age-associated defects in T cell-mediated immunity can increase the risk of cancers, but how aging influences adoptive T-cell therapy (ACT) for cancers remains unclear. Here, using a mouse model of melanoma, we demonstrate that aging diminishes anti-tumor activity of engineered CD8 T cells expressing a tumor-specific T cell receptor (CD8 TCR-T cells) in ACT for solid tumors. Aged CD8 TCR-T cells cannot control tumor growth in either young or aged mice. Aged CD8 TCR-T cells are unable to accumulate efficiently in tumors and have higher tendency to become terminally exhausted T cells with lower expression of endothelial PAS domain-containing protein 1 (Epas1) compared to young cells. Crispr-mediated ablation of Epas1 promotes terminal exhaustion of young CD8 T cells in tumors, diminishing their anti-tumor activity in young mice. Conversely, retroviral expression of Epas1 enhances anti-tumor activity of aged CD8 TCR-T cells. These findings suggest that aging-induced reduction of Epas1 expression impairs anti-tumor activity of CD8 T cells in ACT against solid tumors, which can be therapeutically improved by expression of exogenous Epas1.

引用

页数：17

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