Preclinical study reveals enhanced survival of HLA-deficient engineered regulatory T cells in humanized mice, indicating a viable strategy for off-the-shelf cell therapies.
Key Points
To develop a synthetic NKG2A engager that selectively shields HLA-deficient allogeneic engineered regulatory T cells from natural killer cell-mediated destruction.
Engineered HLA-null regulatory T cells to express a synthetic engager that specifically binds inhibitory NKG2A receptors while bypassing activating NKG2C receptors on natural killer cells.
Tested protection against natural killer cell cytotoxicity in vitro and evaluated in vivo cell persistence for up to 12 weeks in humanized mouse models.
Incorporated the engager construct into a clinically translatable dual-adeno-associated virus delivery system to assess impact on regulatory T cell phenotype and function.
Engager-expressing engineered regulatory T cells exhibited significantly reduced lysis by natural killer cells in vitro compared with previous inhibitory approaches.
Humanized mouse models showed engager-protected regulatory T cells persisted for up to 12 weeks, whereas unprotected allogeneic cells were rapidly cleared.
Dual-AAV delivery preserved regulatory T cell identity and suppressive function while sustaining resistance against host immune-mediated rejection.