Enhanced IL-2 sensitivity for improved TIL therapy efficacy using CD8αMyD88 engineered T-cells 3978

Abstract Description Tumor-infiltrating lymphocyte (TIL) therapy is a form of adoptive cell transfer therapy that has delivered remarkable clinical outcomes in select patients. However, its broader impact is constrained by the dependency of TIL therapy on high-dose (HD) IL2 during manufacturing and clinical administration. HD IL2 can drive TIL dysfunction and cause life-threatening immune-related adverse events in patients. Our lab demonstrated that CD8 T-cell expansion depends on MyD88 signaling, a key adaptor protein in toll-like receptor signaling. Leveraging this, we engineered a synthetic co-receptor, CD8αMyD88 (CM) into CD8 T-cells, which dramatically improved tumor rejection in a B16-F10 melanoma mouse model. This enhanced antitumor efficacy was associated with higher CD8 T-cell proliferation, and elevated expression of the high-affinity IL2 receptor subunit, IL2RA. Hypothesis: CM T-cells have increased sensitivity to IL-2 mediated expansion driven by NFkB-mediated transcription of IL2RA. Results CM T-cells exhibit superior expansion potential across various IL2 concentrations in both healthy donors and TILs. This heightened IL2 sensitivity is mediated by NFkB-driven IL2RA expression which results in amplified and more persistent JAK/STAT signaling. In-vivo, CM TILs achieved robust tumor regression in the B16-F10 melanoma model even at low-dose IL2 – marking a significant advancement toward expanding TIL therapy’s clinical accessibility while mitigating its limitations. Funding Sources Supported by NSF GRFP; R01CA271537 (NCI/NIH); BX004935-01 Dept. of VA Merit Award Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)