Journal Article

DKFZ-2026-02443

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CAR T cell-induced interferon gamma enhances MHC class I expression and sensitizes neuroblastoma to TCR-engineered T cell therapy.

Vitali, A. ; Padlo, J. ; Caramel, C. ; Andersch, L.DKFZ* ; Hartmann, L. M. ; Kath, J. ; Grunewald, L. ; Schwiebert, S. ; Winkler, A. ; Talalai, E. ; Biereder, T. ; Wienke, J. ; Molenaar, J. J. ; Launspach, M.DKFZ* ; Delebinski, C. ; Kern, A. ; Astrahantseff, K. ; Wagner, D. L. ; Willimsky, G.DKFZ* ; Eggert, A. ; Blankenstein, T. ; Anders, K. ; Künkele, A.DKFZ*

2026
Frontiers Media Lausanne

Abstract: 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.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.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.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.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.

Keyword(s): Humans (MeSH) ; Neuroblastoma: therapy (MeSH) ; Neuroblastoma: immunology (MeSH) ; Neuroblastoma: metabolism (MeSH) ; Animals (MeSH) ; Interferon-gamma: metabolism (MeSH) ; Interferon-gamma: immunology (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Receptors, Chimeric Antigen: genetics (MeSH) ; Receptors, Chimeric Antigen: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Histocompatibility Antigens Class I: immunology (MeSH) ; Histocompatibility Antigens Class I: genetics (MeSH) ; Histocompatibility Antigens Class I: metabolism (MeSH) ; Mice (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: metabolism (MeSH) ; Receptors, Antigen, T-Cell: genetics (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Cytotoxicity, Immunologic (MeSH) ; MHC class I low ; T cell therapy ; TCR T cell resistance ; antigen loss ; neuroblastoma ; tumor heterogeneity ; Interferon-gamma ; Receptors, Chimeric Antigen ; Histocompatibility Antigens Class I ; Receptors, Antigen, T-Cell

Note: #DKTKZFB26#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)
2. DKTK BE Exp. und Translationale Tumorimmunologie (BE02)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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