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AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells.

Publication ,  Journal Article
Trillo-Tinoco, J; Sierra, RA; Mohamed, E; Cao, Y; de Mingo-Pulido, Á; Gilvary, DL; Anadon, CM; Costich, TL; Wei, S; Flores, ER; Ruffell, B ...
Published in: Cancer Res
October 1, 2019

Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, Prkaa1, in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5-dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8+ T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer. SIGNIFICANCE: AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

October 1, 2019

Volume

79

Issue

19

Start / End Page

5034 / 5047

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Tumor Escape
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Myeloid-Derived Suppressor Cells
  • Mice
  • Humans
  • Female
  • Cell Differentiation
  • Carcinoma, Ovarian Epithelial
 

Citation

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MLA
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Trillo-Tinoco, J., Sierra, R. A., Mohamed, E., Cao, Y., de Mingo-Pulido, Á., Gilvary, D. L., … Rodriguez, P. C. (2019). AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells. Cancer Res, 79(19), 5034–5047. https://doi.org/10.1158/0008-5472.CAN-19-0880
Trillo-Tinoco, Jimena, Rosa A. Sierra, Eslam Mohamed, Yu Cao, Álvaro de Mingo-Pulido, Danielle L. Gilvary, Carmen M. Anadon, et al. “AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells.Cancer Res 79, no. 19 (October 1, 2019): 5034–47. https://doi.org/10.1158/0008-5472.CAN-19-0880.
Trillo-Tinoco J, Sierra RA, Mohamed E, Cao Y, de Mingo-Pulido Á, Gilvary DL, et al. AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells. Cancer Res. 2019 Oct 1;79(19):5034–47.
Trillo-Tinoco, Jimena, et al. “AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells.Cancer Res, vol. 79, no. 19, Oct. 2019, pp. 5034–47. Pubmed, doi:10.1158/0008-5472.CAN-19-0880.
Trillo-Tinoco J, Sierra RA, Mohamed E, Cao Y, de Mingo-Pulido Á, Gilvary DL, Anadon CM, Costich TL, Wei S, Flores ER, Ruffell B, Conejo-Garcia JR, Rodriguez PC. AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells. Cancer Res. 2019 Oct 1;79(19):5034–5047.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

October 1, 2019

Volume

79

Issue

19

Start / End Page

5034 / 5047

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Tumor Escape
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Myeloid-Derived Suppressor Cells
  • Mice
  • Humans
  • Female
  • Cell Differentiation
  • Carcinoma, Ovarian Epithelial