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Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E1016-25. doi: 10.1073/pnas.1520245113. Epub 2016 Feb 9.

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation.

Author information

1
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
2
Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
3
Division of Biostatistics, Department of Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136;
4
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
5
Division of Hematology/Oncology, Tennessee Valley Healthcare System and Vanderbilt University Medical Center, Nashville, TN 37232.
6
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; lehrlich@austin.utexas.edu.

Abstract

Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.

KEYWORDS:

IGF1R; T-ALL; dendritic cell; leukemia; tumor microenvironment

PMID:
26862168
PMCID:
PMC4776467
DOI:
10.1073/pnas.1520245113
[Indexed for MEDLINE]
Free PMC Article

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