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

Triplett TA, Cardenas KT, Lancaster JN, Hu Z, Selden HJ, Jasso GJ, Balasubramanyam S, Chan K, Li L, Chen X, Marcogliese AN, Davé UP, Love PE, Ehrlich LI
Proc Natl Acad Sci U S A. 2016 113 (8): E1016-25

PMID: 26862168 · PMCID: PMC4776467 · DOI:10.1073/pnas.1520245113

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.

MeSH Terms (14)

Animals Cell Line, Tumor Cell Survival Dendritic Cells Female Humans Male Mice Neoplasm Proteins Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Receptor, Platelet-Derived Growth Factor beta Receptors, Somatomedin Signal Transduction Tumor Microenvironment

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