T cells engineered to express a chimeric β:CD3ζ:MyD88 T cell receptor enhance anti-tumor responses through altering the immunosuppressive tumor microenvironment 4417

Abstract Description The recent FDA approval of a T cell receptor (TCR)-engineered T cell therapy for synovial sarcoma exemplifies the potential of this therapeutic strategy; however, this being the only approved form of the therapy after decades of research highlights the continued need for improvement. Limitations to such adoptive T cell-based strategies include poor T cell function and persistence. This can be mediated by the tumor’s ability to down-regulate machinery necessary for productive T cell activation, as well as the tumor’s ability to foster an immunosuppressive tumor microenvironment. To overcome these limitations, our lab previously developed a chimeric TCR where MyD88—an innate immune signaling adapter protein with robust costimulatory effects on T cells—is appended to the β chain of the TCR via a CD3ζ based linker. We found that T cells engineered to express this β:CD3ζ:MyD88 TCR activated the MyD88 pathway concurrently with TCR activation and exhibited enhanced T cell responses. Here, we show that adoptively transferring β:CD3ζ:MyD88 T cells into a melanoma tumor bearing mouse model promotes a less exhausted phenotype of the tumor infiltrating T cells, a less suppressive tumor microenvironment, and ultimately improves tumor control. These findings provide support that β:CD3ζ:MyD88 T cells improve anti-tumor T cell responses and provide a possible modality for improving on the current state of TCR-engineered T cell therapies. Funding Sources T32A1007405, NIAID R25GM150243 R01CD207913 BX004935-01 VA Merit Award P30CA046934, NCI Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)