Engineering T Cells with a Tumor-Reactive Chimeric T Cell Receptor Reduces Exhaustion and Promotes Persistence to Elicit Enhanced Antitumor Responses

The recent FDA approval of the first T cell receptor-engineered T (TCR-T) cell cancer therapy has solidified the treatment as a viable therapeutic strategy. However, only a fraction of patients who received this treatment achieved substantial and long-lasting responses, highlighting the need to understand the molecular underpinnings of these responses and develop more effective strategies to improve this therapy. Previous research has demonstrated that the activation of MyD88 signaling in tumor-specific T cells functions as a robust costimulatory signaling pathway that promotes effective antitumor T cell responses. Here, we developed a strategy for improving TCR-T cell therapies by creating a synthetic TCR in which the intracellular domain of CD3ζ and a modified MyD88 are appended to the β-chain of a tumor-reactive TCR. The β:CD3ζ:MyD88 TCR activated MyD88 signaling in a tumor-antigen/TCR-specific manner, and β:CD3ζ:MyD88 TCR-T cells exhibited enhanced functionality and a reduced propensity to become exhausted. Furthermore, MyD88 signaling promoted T cell persistence and expansion in vitro. In vivo, tumor-infiltrating β:CD3ζ:MyD88 TCR-T cells skewed the immunosuppressive tumor microenvironment toward a less immunosuppressive state. Finally, β:CD3ζ:MyD88 TCR-T cells substantially delayed tumor growth kinetics in a melanoma model. These findings introduce an approach for improving TCR-dependent T cell responses by directly appending signaling domains to the full-length TCR and exemplify the utility of activating MyD88 signaling in tumor-specific T cells.