Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ

Schürch, Christian; Riether, Carsten; Amrein, Michael A.; Ochsenbein, Adrian F. (2013). Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ. Journal of experimental medicine, 210(3), pp. 605-621. Rockefeller University Press 10.1084/jem.20121229

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia arising from the oncogenic break point cluster region/Abelson murine leukemia viral oncogene homolog 1 translocation in hematopoietic stem cells (HSCs), resulting in a leukemia stem cell (LSC). Curing CML depends on the eradication of LSCs. Unfortunately, LSCs are resistant to current treatment strategies. The host’s immune system is thought to contribute to disease control, and several immunotherapy strategies are under investigation. However, the interaction of the immune system with LSCs is poorly defined. In the present study, we use a murine CML model to show that LSCs express major histocompatibility complex (MHC) and co-stimulatory molecules and are recognized and killed by leukemia-specific CD8+ effector CTLs in vitro. In contrast, therapeutic infusions of effector CTLs into CML mice in vivo failed to eradicate LSCs but, paradoxically, increased LSC numbers. LSC proliferation and differentiation was induced by CTL-secreted IFN-γ. Effector CTLs were only able to eliminate LSCs in a situation with minimal leukemia load where CTL-secreted IFN-γ levels were low. In addition, IFN-γ increased proliferation and colony formation of CD34+ stem/progenitor cells from CML patients in vitro. Our study reveals a novel mechanism by which the immune system contributes to leukemia progression and may be important to improve T cell–based immunotherapy against leukemia.

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

UniBE Contributor:

Schürch, Christian; Riether, Carsten; Amrein, Michael and Ochsenbein, Adrian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-1007

Publisher:

Rockefeller University Press

Language:

English

Submitter:

Marianne Zahn

Date Deposited:

12 May 2014 11:18

Last Modified:

13 Jul 2015 09:36

Publisher DOI:

10.1084/jem.20121229

PubMed ID:

23401488

BORIS DOI:

10.7892/boris.45043

URI:

https://boris.unibe.ch/id/eprint/45043

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