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

Area of Science:

• Immunology
• Oncology
• Aging Research

Background:

• Age-associated decline in T cell immunity increases cancer risk.
• The impact of aging on adoptive T-cell therapy (ACT) for cancer is not well understood.

Purpose of the Study:

• To investigate how aging affects the anti-tumor efficacy of engineered CD8 T cells in ACT for solid tumors.
• To explore the role of endothelial PAS domain-containing protein 1 (Epas1) in age-related T cell dysfunction during ACT.

Main Methods:

• Utilized a mouse model of melanoma.
• Engineered CD8 T cells expressing a tumor-specific T cell receptor (CD8 TCR-T cells) were used for ACT.
• CRISPR-mediated gene editing and retroviral expression were employed to manipulate Epas1 levels.

Main Results:

• Aged CD8 TCR-T cells exhibited diminished anti-tumor activity and impaired tumor infiltration compared to young cells.
• Aged T cells showed increased terminal exhaustion and lower Epas1 expression.
• CRISPR-mediated ablation of Epas1 in young T cells promoted exhaustion and reduced anti-tumor function.
• Exogenous Epas1 expression enhanced the anti-tumor activity of aged CD8 TCR-T cells.

Conclusions:

• Aging-induced reduction in Epas1 expression impairs the anti-tumor activity of CD8 T cells in ACT for solid tumors.
• Therapeutic enhancement of Epas1 expression presents a potential strategy to improve ACT efficacy in aged individuals.