Bone marrow-derived mesenchymal stromal cells obstruct AML-targeting CD8+ clonal effector and CAR T-cell function while promoting a senescence-associated phenotype
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Published:2024-01
Issue:1
Volume:73
Page:
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ISSN:0340-7004
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Container-title:Cancer Immunology, Immunotherapy
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language:en
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Short-container-title:Cancer Immunol Immunother
Author:
Towers Russell,Trombello Lidia,Fusenig Maximilian,Tunger Antje,Baumann Anna-Lena,Savoldelli Roberto,Wehner Rebekka,Fasslrinner Frederick,Arndt Claudia,Dazzi Francesco,Von Bonin Malte,Feldmann Anja,Bachmann Michael P.,Wobus Manja,Schmitz Marc,Bornhäuser Martin
Abstract
AbstractBone marrow mesenchymal stromal cells (MSCs) have been described as potent regulators of T-cell function, though whether they could impede the effectiveness of immunotherapy against acute myeloid leukemia (AML) is still under investigation. We examine whether they could interfere with the activity of leukemia-specific clonal cytotoxic T-lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells, as well as whether the immunomodulatory properties of MSCs could be associated with the induction of T-cell senescence. Co-cultures of leukemia-associated Wilm’s tumor protein 1 (WT1) and tyrosine-protein kinase transmembrane receptor 1 (ROR1)-reactive CTLs and of CD123-redirected switchable CAR T cells were prepared in the presence of MSCs and assessed for cytotoxic potential, cytokine secretion, and expansion. T-cell senescence within functional memory sub-compartments was investigated for the senescence-associated phenotype CD28−CD57+ using unmodified peripheral blood mononuclear cells. We describe inhibition of expansion of AML-redirected switchable CAR T cells by MSCs via indoleamine 2,3-dioxygenase 1 (IDO-1) activity, as well as reduction of interferon gamma (IFNγ) and interleukin-2 (IL-2) release. In addition, MSCs interfered with the secretory potential of leukemia-associated WT1- and ROR1-targeting CTL clones, inhibiting the release of IFNγ, tumor necrosis factor alpha, and IL-2. Abrogated T cells were shown to retain their cytolytic activity. Moreover, we demonstrate induction of a CD28loCD27loCD57+KLRG1+ senescent T-cell phenotype by MSCs. In summary, we show that MSCs are potent modulators of anti-leukemic T cells, and targeting their modes of action would likely be beneficial in a combinatorial approach with AML-directed immunotherapy.
Funder
Mildred Scheel Early Career Center Technische Universität Dresden
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Immunology,Immunology and Allergy
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