Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance.
The transcription factors and proto-oncogenes STAT3 and STAT5 are highly activated in hematological malignancies and represent promising therapeutic targets. Whereas the importance of STAT5 as tumor promoter is beyond doubt, the role of STAT3 in hematological cancers is less well understood. Both, enforced as well as attenuated expression of STAT3 were reported in hematopoietic malignancies. Recent evidence implicates STAT3 as key player for tumor immune surveillance as it both mediates the production of and response to inflammatory cytokines. Here we investigated the effects of STAT3 deletion in a BCR/ABL-induced lymphoma model, which is tightly controlled by natural killer (NK) cells in vivo. Upon STAT3 deletion tumor growth is significantly enhanced when compared to STAT3-expressing controls. The increased tumor size upon loss of STAT3 was accompanied by reduced NK cell infiltration and decreased levels of the cytokine IFN-γ and the chemokine RANTES. Upon transplantation into NK cell-deficient mice differences in lymphoma size were abolished indicating that STAT3 expression in the tumor cells controls NK cell-dependent tumor surveillance. Our findings indicate that STAT3 inhibition in lymphoma patients will impair NK cell-mediated tumor surveillance, which needs to be taken into account when testing STAT3 inhibitors in preclinical or clinical trials.
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Veterinaerplatz 1, Vienna 1210, Austria. eva-maria.putz@vetmeduni.ac.at.
Eva Maria
EM
Putz
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna (MUV), Waehringer Strasse 13A, Vienna 1090, Austria. maria.holzl@ki.se.
Maria Agnes
MA
Hoelzl
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Veterinaerplatz 1, Vienna 1210, Austria. julia.baeck@gmx.at.
Julia
J
Baeck
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Veterinaerplatz 1, Vienna 1210, Austria. zsuzsanna.bago-horvath@vetmeduni.ac.at.
Zsuzsanna
Z
Bago-Horvath
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna (MUV), Waehringer Strasse 13A, Vienna 1090, Austria. christian.schuster@dkfz-heidelberg.de.
Christian
C
Schuster
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Veterinaerplatz 1, Vienna 1210, Austria. brian.reichholf@gmail.com.
Brian
B
Reichholf
Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34, Salzburg 5020, Austria. daniela.kern@sbg.ac.at.
Daniela
D
Kern
Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34, Salzburg 5020, Austria. fritz.aberger@sbg.ac.at.
Fritz
F
Aberger
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Veterinaerplatz 1, Vienna 1210, Austria. veronika.sexl@vetmeduni.ac.at.
Veronika
V
Sexl
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Veterinaerplatz 1, Vienna 1210, Austria. andrea.hoelbl@vetmeduni.ac.at.
Andrea
A
Hoelbl-Kovacic