Colony-Stimulating Factor 1 Receptor (CSF1R) Activates AKT/mTOR Signaling and Promotes T-Cell Lymphoma Viability

• Published in: Clinical cancer research 2020-02, Vol.26 (3), p.690-703
• Main Authors: Murga-Zamalloa, Carlos, Rolland, Delphine C M, Polk, Avery, Wolfe, Ashley, Dewar, Hiran, Chowdhury, Pinki, Onder, Ozlem, Dewar, Rajan, Brown, Noah A, Bailey, Nathanael G, Inamdar, Kedar, Lim, Megan S, Elenitoba-Johnson, Kojo S J, Wilcox, Ryan A
• Format: Article
• Language: English
• Subjects: Aminopyridines - pharmacology; Animals; Cell Line, Tumor; Gene Expression Profiling - methods; Humans; Lymphoma, T-Cell, Peripheral - drug therapy; Lymphoma, T-Cell, Peripheral - metabolism; Lymphoma, T-Cell, Peripheral - pathology; Macrophage Colony-Stimulating Factor - metabolism; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Pyrroles - pharmacology; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1486

Peripheral T-cell lymphomas are clinically aggressive and usually fatal, as few complete or durable remissions are achieved with currently available therapies. Recent evidence supports a critical role for lymphoma-associated macrophages during T-cell lymphoma progression, but the specific signals involved in the cross-talk between malignant T cells and their microenvironment are poorly understood. Colony-stimulator factor 1 receptor (CSF1R, CD115) is required for the homeostatic survival of tissue-resident macrophages. Interestingly, its aberrant expression has been reported in a subset of tumors. In this article, we evaluated its expression and oncogenic role in T-cell lymphomas. Loss-of-function studies, including pharmacologic inhibition with a clinically available tyrosine kinase inhibitor, pexidartinib, were performed in multiple and models. In addition, proteomic and genomic screenings were performed to discover signaling pathways that are activated downstream of CSF1R signaling. We observed that CSF1R is aberrantly expressed in many T-cell lymphomas, including a significant number of peripheral and cutaneous T-cell lymphomas. Colony-stimulating factor 1 (CSF1), in an autocrine or paracrine-dependent manner, leads to CSF1R autophosphorylation and activation in malignant T cells. Furthermore, CSF1R signaling was associated with significant changes in gene expression and in the phosphoproteome, implicating PI3K/AKT/mTOR in CSF1R-mediated T-cell lymphoma growth. We also demonstrated that inhibition of CSF1R and models is associated with decreased T-cell lymphoma growth. Collectively, these findings implicate CSF1R in T-cell lymphomagenesis and have significant therapeutic implications.