| Autor: |
Anderson, Victoria E., Brilha, Sara S., Weber, Anika M., Pachnio, Annette, Wiedermann, Guy E., Dauleh, Sumaya, Ahmed, Tina, Pope, George R., Quinn, Laura L., Docta, Roslin Y., Quattrini, Adriano, Masters, Siobhan, Cartwright, Neil, Viswanathan, Preetha, Melchiori, Luca, Rice, Louise V., Sevko, Alexandra, Gueguen, Claire, Saini, Manoj, Tavano, Barbara, Abbott, Rachel J.M., Silk, Jonathan D., Laugel, Bruno, Sanderson, Joseph P., Gerry, Andrew B. |
| Zdroj: |
Journal of Immunotherapy; May 2023, Vol. 46 Issue: 4 p132-144, 13p |
| Abstrakt: |
Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In the present study, we investigated one such approach: T cells were transduced with a lentiviral vector to coexpress an affinity-enhanced HLA class I–restricted TCR directed against MAGE-A4 alongside a CD8α coreceptor. We hypothesized that this approach would enhance CD4+T-cell helper and effector functions, possibly leading to a more potent antitumor response. Activation of transduced CD4+T cells was measured by detecting CD40 ligand expression on the surface and cytokine and chemokine secretion from CD4+T cells and dendritic cells cultured with melanoma-associated antigen A4+tumor cells. In addition, T-cell cytotoxic activity against 3-dimensional tumor spheroids was measured. Our data demonstrated that CD4+T cells coexpressing the TCR and CD8α coreceptor displayed enhanced responses, including CD40 ligand expression, interferon-gamma secretion, and cytotoxic activity, along with improved dendritic cell activation. Therefore, our study supports the addition of the CD8α coreceptor to HLA class I–restricted TCR-engineered T cells to enhance CD4+T-cell functions, which may potentially improve the depth and durability of antitumor responses in patients. |
| Databáze: |
Supplemental Index |
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