STAT3-And STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells

Peter A. Cohen, Gary K. Koski, Brian J. Czerniecki, Kevin D. Bunting, Xin Yuan Fu, Zhengqi Wang, Wen Jun Zhang, Charles S. Carter, Mohamed Awad, Christopher A. Distel, Hassan Nagem, Christopher C. Paustian, Terrence D. Johnson, John F. Tisdale, Suyu Shu

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Abstract

The clinical outcomes of dendritic cell (DC)-based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34 pos cells to single-agent granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that failed to mature in the absence of further exogenous signals. In contrast, Flt3L induced nearly global differentiation of CD34 Pos cells into spontaneously maturing DCs. IL-6 synergized with Flt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGFβ with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L plus IL-6, then GMCSF, selects for multilog expansion, programming, and DC1 polarization of tumor-competent DCs from CD34 Pos cells.

Original languageEnglish
Pages (from-to)1832-1843
Number of pages12
JournalBlood
Volume112
Issue number5
DOIs
StatePublished - Sep 1 2008

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Dendritic Cells
Tumors
Granulocyte-Macrophage Colony-Stimulating Factor
Polarization
Interleukin-6
Neoplasms
Cell Differentiation
Chemical activation
T-cells
Licensure
Immunosuppressive Agents
Immunotherapy
T-Lymphocytes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cohen, P. A., Koski, G. K., Czerniecki, B. J., Bunting, K. D., Fu, X. Y., Wang, Z., ... Shu, S. (2008). STAT3-And STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells. Blood, 112(5), 1832-1843. https://doi.org/10.1182/blood-2007-12-130138

STAT3-And STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells. / Cohen, Peter A.; Koski, Gary K.; Czerniecki, Brian J.; Bunting, Kevin D.; Fu, Xin Yuan; Wang, Zhengqi; Zhang, Wen Jun; Carter, Charles S.; Awad, Mohamed; Distel, Christopher A.; Nagem, Hassan; Paustian, Christopher C.; Johnson, Terrence D.; Tisdale, John F.; Shu, Suyu.

In: Blood, Vol. 112, No. 5, 01.09.2008, p. 1832-1843.

Research output: Contribution to journalArticle

Cohen, PA, Koski, GK, Czerniecki, BJ, Bunting, KD, Fu, XY, Wang, Z, Zhang, WJ, Carter, CS, Awad, M, Distel, CA, Nagem, H, Paustian, CC, Johnson, TD, Tisdale, JF & Shu, S 2008, 'STAT3-And STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells', Blood, vol. 112, no. 5, pp. 1832-1843. https://doi.org/10.1182/blood-2007-12-130138
Cohen, Peter A. ; Koski, Gary K. ; Czerniecki, Brian J. ; Bunting, Kevin D. ; Fu, Xin Yuan ; Wang, Zhengqi ; Zhang, Wen Jun ; Carter, Charles S. ; Awad, Mohamed ; Distel, Christopher A. ; Nagem, Hassan ; Paustian, Christopher C. ; Johnson, Terrence D. ; Tisdale, John F. ; Shu, Suyu. / STAT3-And STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells. In: Blood. 2008 ; Vol. 112, No. 5. pp. 1832-1843.
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abstract = "The clinical outcomes of dendritic cell (DC)-based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34 pos cells to single-agent granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that failed to mature in the absence of further exogenous signals. In contrast, Flt3L induced nearly global differentiation of CD34 Pos cells into spontaneously maturing DCs. IL-6 synergized with Flt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGFβ with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L plus IL-6, then GMCSF, selects for multilog expansion, programming, and DC1 polarization of tumor-competent DCs from CD34 Pos cells.",
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AU - Cohen, Peter A.

AU - Koski, Gary K.

AU - Czerniecki, Brian J.

AU - Bunting, Kevin D.

AU - Fu, Xin Yuan

AU - Wang, Zhengqi

AU - Zhang, Wen Jun

AU - Carter, Charles S.

AU - Awad, Mohamed

AU - Distel, Christopher A.

AU - Nagem, Hassan

AU - Paustian, Christopher C.

AU - Johnson, Terrence D.

AU - Tisdale, John F.

AU - Shu, Suyu

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N2 - The clinical outcomes of dendritic cell (DC)-based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34 pos cells to single-agent granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that failed to mature in the absence of further exogenous signals. In contrast, Flt3L induced nearly global differentiation of CD34 Pos cells into spontaneously maturing DCs. IL-6 synergized with Flt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGFβ with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L plus IL-6, then GMCSF, selects for multilog expansion, programming, and DC1 polarization of tumor-competent DCs from CD34 Pos cells.

AB - The clinical outcomes of dendritic cell (DC)-based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34 pos cells to single-agent granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that failed to mature in the absence of further exogenous signals. In contrast, Flt3L induced nearly global differentiation of CD34 Pos cells into spontaneously maturing DCs. IL-6 synergized with Flt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGFβ with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L plus IL-6, then GMCSF, selects for multilog expansion, programming, and DC1 polarization of tumor-competent DCs from CD34 Pos cells.

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