Abstract: 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.
Keywords: STAT3; lymphoma; BCR/ABL; NK cells; tumor immune surveillance
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Putz, E.M.; Hoelzl, M.A.; Baeck, J.; Bago-Horvath, Z.; Schuster, C.; Reichholf, B.; Kern, D.; Aberger, F.; Sexl, V.; Hoelbl-Kovacic, A. Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance. Cancers 2014, 6, 193-210.
Putz EM, Hoelzl MA, Baeck J, Bago-Horvath Z, Schuster C, Reichholf B, Kern D, Aberger F, Sexl V, Hoelbl-Kovacic A. Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance. Cancers. 2014; 6(1):193-210.
Putz, Eva M.; Hoelzl, Maria A.; Baeck, Julia; Bago-Horvath, Zsuzsanna; Schuster, Christian; Reichholf, Brian; Kern, Daniela; Aberger, Fritz; Sexl, Veronika; Hoelbl-Kovacic, Andrea. 2014. "Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance." Cancers 6, no. 1: 193-210.