Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells.

Hinterbrandner, Magdalena; Rubino, Viviana; Stoll, Carina; Forster, Stefan; Schnüriger, Noah Samuel; Radpour, Ramin; Bärlocher, Gabriela M.; Ochsenbein, Adrian F.; Riether, Carsten (2021). Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells. JCI insight, 6(23) JCI Insight 10.1172/jci.insight.151797

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Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by cytotoxic CD8+ T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML bone marrow (BM), protected LSCs from MHC-class I dependent CD8+ CTL-mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4-signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL-mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulator of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost anti-leukemic immunity in CML.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Hinterbrandner, Magdalena; Rubino, Viviana; Stoll, Carina Manon; Forster, Stefan; Schnüriger, Noah Samuel; Radpour, Ramin; Bärlocher, Gabriela Maria; Ochsenbein, Adrian and Riether, Carsten

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2379-3708

Publisher:

JCI Insight

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

01 Dec 2021 11:46

Last Modified:

10 Dec 2021 00:14

Publisher DOI:

10.1172/jci.insight.151797

PubMed ID:

34727093

Uncontrolled Keywords:

Cancer immunotherapy Hematology Leukemias Stem cells

BORIS DOI:

10.48350/160879

URI:

https://boris.unibe.ch/id/eprint/160879

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