Enhancing Efficacy of TCR-engineered CD4+ T Cells Via Coexpression of CD8α

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 CD8 alpha 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 CD8 alpha 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 CD8 alpha 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.