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

Gulfiya Kadyrzhanova1, Miho Tamai1, Shukla Sarkar1

  • 1Immune Signal Unit, Okinawa Institute of Science and Technology, Graduate University (OIST), Okinawa, Japan.

Frontiers in Immunology
|February 10, 2025
PubMed

Insights

Aging impairs the effectiveness of adoptive T-cell therapy (ACT) for cancer by reducing CD8 T cell anti-tumor activity. Enhancing Epas1 expression in aged T cells can restore their cancer-fighting capabilities.

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.
Keywords:
CD8 T cellsEpas1adoptive T-cell therapyagingcancer

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