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

Abstract

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.

Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma

“…To enhance persistence and function of CD4 + T TCR-MCC1 , we modified the transgene by adding CD8αβ to support peptide-HLA recognition by CD4 T cells. 39 Additionally, we employed the CD200R-CD28 immunomodulatory fusion protein to provide CD4 and CD8 T TCR-MCC1 cells with HLA-independent stimuli. 40 CD200 is expressed in 84% of MCC, 41 and all seven patients in our cohort ( Figure 6a ).…”

Cancer testis antigens: Emerging therapeutic targets leveraging genomic instability in cancer

“…Preclinical research further suggests that the addition of the CD8α receptor to an affinity-enhanced HLA class I-restricted TCR against MAGE-A4 can enhance CD4+ T helper and effector functions which could improve the depth and durability of anti-tumor immune responses. 215 …”

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells

“…Tumor-specific CD4 + T cells can be generated by using MHC-I molecular restrictive TCR, which enhances the tumor-killing ability of specific CD8 + T cells. The reason for this phenomenon may be related to the secretion of various immune factors by CD4 + T cells [ 344 , 349 , 562 ]. In addition, antigen-specific CD4 + T cells have also been used to treat tumor patients [ 563 – 565 ].…”