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.
Highlights
Tumorigenesis involves both tumor-intrinsic alterations as well as modulations of the tumor environment favoring tumor growth and maintenance
Single cell suspensions of BM derived from Stat3fl/fl Mx1-Cre and wild-type mice were infected retrovirally with the BCR/ABLp185 oncogene
In an additional approach STAT3 was reduced using lentiviral knockdown in two independently derived wild-type pro-B cell lines (#1 being transformed by v-ABLp160, #4 by BCR/ABLp185). This resulted in a STAT3 knockdown of 64% and 48%
Summary
Tumorigenesis involves both tumor-intrinsic alterations as well as modulations of the tumor environment favoring tumor growth and maintenance. Constitutive activation of the JAK/STAT pathway was described in patient-derived BCR/ABL+ leukemic cells [17,18,19,20]. Tumor formation occurred spontaneously and in the absence of a driving oncogene: STAT3αC alone sufficed to induce leukemia. STAT3 induces target gene transcription of pro-survival and proliferative genes such as Bcl or cyclin D1 that promote tumor growth and survival. Another layer of complexity comes from the fact that STAT3 is critically involved in the production of immune-modulatory cytokines such as IL-6, IL-10, IL-17 and IFN-γ [33,34] and pro-angiogenic factors like VEGF [35]. Pro-inflammatory cytokines such as IL-6, IFN-γ, TNF-α and RANTES are markedly reduced in STAT3-deficient tumors
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