Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors
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 expressin...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1484303/full |
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| author | Gulfiya Kadyrzhanova Miho Tamai Shukla Sarkar Rajkumar Singh Kalra Hiroki Ishikawa |
| author_facet | Gulfiya Kadyrzhanova Miho Tamai Shukla Sarkar Rajkumar Singh Kalra Hiroki Ishikawa |
| author_sort | Gulfiya Kadyrzhanova |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-71418c630b82499a899e4ffd77d188d1 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-71418c630b82499a899e4ffd77d188d12025-01-24T08:46:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.14843031484303Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumorsGulfiya KadyrzhanovaMiho TamaiShukla SarkarRajkumar Singh KalraHiroki IshikawaAge-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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1484303/fullagingadoptive T-cell therapycancerCD8 T cellsEpas1 |
| spellingShingle | Gulfiya Kadyrzhanova Miho Tamai Shukla Sarkar Rajkumar Singh Kalra Hiroki Ishikawa Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors Frontiers in Immunology aging adoptive T-cell therapy cancer CD8 T cells Epas1 |
| title | Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors |
| title_full | Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors |
| title_fullStr | Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors |
| title_full_unstemmed | Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors |
| title_short | Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors |
| title_sort | aging impairs cd8 t cell responses in adoptive t cell therapy against solid tumors |
| topic | aging adoptive T-cell therapy cancer CD8 T cells Epas1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1484303/full |
| work_keys_str_mv | AT gulfiyakadyrzhanova agingimpairscd8tcellresponsesinadoptivetcelltherapyagainstsolidtumors AT mihotamai agingimpairscd8tcellresponsesinadoptivetcelltherapyagainstsolidtumors AT shuklasarkar agingimpairscd8tcellresponsesinadoptivetcelltherapyagainstsolidtumors AT rajkumarsinghkalra agingimpairscd8tcellresponsesinadoptivetcelltherapyagainstsolidtumors AT hirokiishikawa agingimpairscd8tcellresponsesinadoptivetcelltherapyagainstsolidtumors |