Frontiers in immunology · 2026
CAR T cell-induced interferon gamma enhances MHC class I expression and sensitizes neuroblastoma to TCR-engineered T cell therapy.
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Vitali Alice, Padlo Jennie, Caramel Carlotta, Andersch Lena, Hartmann Laura M, Kath Jonas, Grunewald Laura, Schwiebert Silke, Winkler Anika, Talalai Efrosiinia, Biereder Tabea, Wienke Judith, Molenaar Jan J, Launspach Michael, Delebinski Catharina, Kern Anton, Astrahantseff Kathy, Wagner Dimitrios L, Willimsky Gerald, Eggert Angelika, Blankenstein Thomas, Anders Kathleen, Künkele Annette
Аннотация
BACKGROUND: T cell receptor (TCR)-engineered T cells target antigens presented on major histocompatibility complex (MHC) class I molecules. MHC class I expression is often low in childhood tumors such as neuroblastoma but can be stimulated by interferon gamma (IFNγ). Chimeric antigen receptor (CAR) T cell effector function, including IFNγ production, is MHC class I-independent.
AIM: We aimed to enhance neuroblastoma immunotherapy by combining CAR- and TCR-engineered T cells. Our strategy exploits CAR T cell-derived effector molecules, including IFNγ, to increase tumor cell MHC class I expression and thereby enhance subsequent TCR T cell activity.
METHODS: IFNγ-mediated induction and persistence of MHC class I expression were analyzed in neuroblastoma cell lines by flow cytometry. Primary human T cells were engineered to express either a high-affinity TCR targeting the cancer testis antigen NY-ESO-1 or an L1CAM-targeted CAR. Cytotoxic activity of CAR and TCR T cells, applied alone or sequentially, was quantified against LAN-1 neuroblastoma cells using IncuCyte-based real-time killing assays. To model heterogeneous antigen expression, mixed tumor populations containing L1CAM-positive and CRISPR/Cas9-generated L1CAM-knockout cells were analyzed. In vivo MHC class I upregulation was assessed in a human tumor xenograft model following treatment with human L1CAM-CAR T cells and in a syngeneic tumor model following treatment with GD2-CAR T cells.
RESULTS: NY-ESO-1 TCR T cells alone showed limited cytotoxicity against LAN-1 cells in vitro, whereas L1CAM-CAR T cell pretreatment increased MHC class I expression and enhanced subsequent TCR-mediated killing. In tumor cells with heterogeneous CAR antigen expression, CAR T cell recognition of antigen-positive cells induced HLA-A*02 upregulation across the tumor population, enabling subsequent NY-ESO-1 TCR T cell recognition of cells not directly recognized by CAR T cells. Exploratory in vivo analyses further showed increased tumor MHC class I expression following CAR T cell treatment, providing preliminary evidence of CAR T cell-mediated inflammatory priming in vivo.
CONCLUSION: Sequential CAR- and TCR-engineered T cell therapy may help overcome limitations imposed by low MHC class I and heterogeneous antigen expression in neuroblastoma, supporting further investigation of this combinatorial strategy.
AIM: We aimed to enhance neuroblastoma immunotherapy by combining CAR- and TCR-engineered T cells. Our strategy exploits CAR T cell-derived effector molecules, including IFNγ, to increase tumor cell MHC class I expression and thereby enhance subsequent TCR T cell activity.
METHODS: IFNγ-mediated induction and persistence of MHC class I expression were analyzed in neuroblastoma cell lines by flow cytometry. Primary human T cells were engineered to express either a high-affinity TCR targeting the cancer testis antigen NY-ESO-1 or an L1CAM-targeted CAR. Cytotoxic activity of CAR and TCR T cells, applied alone or sequentially, was quantified against LAN-1 neuroblastoma cells using IncuCyte-based real-time killing assays. To model heterogeneous antigen expression, mixed tumor populations containing L1CAM-positive and CRISPR/Cas9-generated L1CAM-knockout cells were analyzed. In vivo MHC class I upregulation was assessed in a human tumor xenograft model following treatment with human L1CAM-CAR T cells and in a syngeneic tumor model following treatment with GD2-CAR T cells.
RESULTS: NY-ESO-1 TCR T cells alone showed limited cytotoxicity against LAN-1 cells in vitro, whereas L1CAM-CAR T cell pretreatment increased MHC class I expression and enhanced subsequent TCR-mediated killing. In tumor cells with heterogeneous CAR antigen expression, CAR T cell recognition of antigen-positive cells induced HLA-A*02 upregulation across the tumor population, enabling subsequent NY-ESO-1 TCR T cell recognition of cells not directly recognized by CAR T cells. Exploratory in vivo analyses further showed increased tumor MHC class I expression following CAR T cell treatment, providing preliminary evidence of CAR T cell-mediated inflammatory priming in vivo.
CONCLUSION: Sequential CAR- and TCR-engineered T cell therapy may help overcome limitations imposed by low MHC class I and heterogeneous antigen expression in neuroblastoma, supporting further investigation of this combinatorial strategy.