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Winter, L.* ; Pawlowsky, L.* ; Muth, A.* ; Neumann, A.* ; White, K.* ; Kazerani, M.* ; Nixdorf, D.* ; Brauchle, B.* ; Rohrbacher, L.* ; Hänel, G.* ; Petrera, A. ; Briem, E.* ; Hoffmann, G.* ; Janert, T.* ; Carlini, E.* ; Gottschlich, A.* ; Spiekermann, K.* ; Straub, T.* ; Kischel, R.* ; Kobold, S.* ; Andreeff, M.* ; Buecklein, V.L.* ; Subklewe, M.*

TP53 deficiency in AML induces resistance to T-cell engagers through an immunosuppressive secretome.

Leukemia, DOI: 10.1038/s41375-026-02991-6 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Bispecific T-cell engagers (BiTE® molecules) have transformed the treatment of B-cell malignancies, yet clinical activity in AML has been modest. Resistance is driven in part by the genetic heterogeneity of AML, most notably TP53 mutations, present in 10-15% of de novo and up to 25% of therapy-related AML. Thus, we hypothesized that TP53 aberrations in AML contribute to cell-intrinsic and extrinsic resistance against T-cell-based immunotherapy. Cytotoxicity against TP53-deleted (DEL) primary AML cells and TP53-knockdown (KD) AML cell lines was reduced in co-cultures with T cells stimulated with the BiTE molecule AMG 330 (CD3×CD33). In addition, T-cell proliferation and proinflammatory cytokine secretion was impaired in co-cultures with TP53 KD cells. Transwell assays identified the secretome of TP53 KD AML cells as a key contributor to the immunosuppressive effects. Proteomic analysis revealed TGF-β1 in TP53 KD co-cultures as a mediator of T-cell suppression. RNA sequencing of T cells co-cultured with TP53 KD cells uncovered a transcriptional shift toward a senescent cell cycle profile. Our data collectively identify the immunosuppressive secretome of TP53-deficient AML as a key barrier to T-cell-engaging immunotherapies, underscoring an unmet clinical need for strategies able to restore T-cell function in TP53 KD AML.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mediator ; Proinflammatory Cytokine ; Leukemia ; Cell Culture ; Cytokine ; Cytotoxicity ; Secretion ; Haematopoiesis; Growth-factor-beta; Inhibition; Leukemia
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Zeitschrift Leukemia
Verlag Springer
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) CF Metabolomics & Proteomics (CF-MPC)
Förderungen i-Target: immunotargeting of cancer" (funded by the Elite Network of Bavaria)
Deutsche Jos Carreras Leukmie Stiftung international doctoral program bdquo
SFB TRR 338 ("LETSImmun, project no. 452881907 B01) research funding from Amgen Bavarian Cancer Research Center (BZKF) BMBF in the framework of the Cluster4Future program (Cluster for Nucleic Acid Therapeutics Munich, CNATM) (Project ID: (03ZU1201AA) Deut
Deutsche Forschungsgemeinschaft (DFG, grant number NI 2469/1-1)
Else Krner-Fresenius-Stiftung (IOLIN)
Deutsche Forschungsgemeinschaft (DFG, GO 3823/1-1)
i-Targ
German Research Foundation) within the SFB TRR 338 ("LETSImmun, project no. 452881907 B01) DFG grant number: KO5055-2-1 and KO5055/3-1 Bavarian Cancer Research Center (BZKF) international doctoral program bdquo
Deutsche Forschungsgemeinschaft (DFG