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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1484303
This article is part of the Research Topic Mechanisms and Therapeutic Opportunities of T Cell Impairment in Cancer Immunity and Immunotherapy View all 6 articles

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

Provisionally accepted
Gulfiya Kadyrzhanova Gulfiya Kadyrzhanova Miho Tamai Miho Tamai Shukla Sarkar Shukla Sarkar Rajkumar Singh Rajkumar Singh Hiroki Ishikawa Hiroki Ishikawa *
  • Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan

The final, formatted version of the article will be published soon.

    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.

    Keywords: Aging, Adoptive T-Cell Therapy, Cancer, CD8 T cells, EPAS1

    Received: 21 Aug 2024; Accepted: 02 Jan 2025.

    Copyright: © 2025 Kadyrzhanova, Tamai, Sarkar, Singh and Ishikawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Hiroki Ishikawa, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan

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