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

Abstract

Purpose: 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.Experimental Design: Loss-of-function studies, including pharmacologic inhibition with a clinically available tyrosine kinase inhibitor, pexidartinib, were performed in multiple in vitro and in vivo models. In addition, proteomic and genomic screenings were performed to discover signaling pathways that are activated downstream of CSF1R signaling.Results: 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 in vivo and in vitro models is associated with decreased T-cell lymphoma growth.Conclusions: Collectively, these findings implicate CSF1R in T-cell lymphomagenesis and have significant therapeutic implications.

CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis

“…As downstream effectors of TAMs, M2-induced cytokine IL-10, as well as immunosuppressive factors B7-H4 and CSF1R, were increased correspondingly, which may inhibit the cytotoxic activity of tumor-associated antigen-specific T cells and promote lymphoma cell evasion. 44 – 46 Our data demonstrated that the FBXW7-NOTCH-CCL2/CSF1 axis as an important mechanism of tumor progression provoked by TAMs in DLBCL. Considering that the NOTCH inhibitor has an off-target effect and is toxic if applied systemically, designing a more effective way to target CCL2/CSF1 can be a feasible immune intervention for DLBCL treatment.…”

CSF1/CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization

“…CSF1R signaling is associated with significant changes in gene expression and the phosphoproteome, which indicates that the PI3K/AKT/mTOR axis promotes CSF1R-mediated T-cell lymphoma growth. 16 The transcription factor FOXO1 is downstream of PI3K/AKT in macrophages, 17 and it facilitates M2 polarization. 12 Therefore we detected the effects of CSF1 derived from HCVECs on the PI3K/AKT/FOXO1 axis in human macrophages.…”

Integrative Statistics, Machine Learning and Artificial Intelligence Neural Network Analysis Correlated CSF1R with the Prognosis of Diffuse Large B-Cell Lymphoma

“…CSF1R has a role in regulating the homeostatic survival of the tumor-associated macrophages (TAMs). TAMs are relevant because they promote tumorigenesis of many types of cancer, including non-Hodgkin lymphomas [23,[35][36][37][38]. Therefore, CSF1R is a potentially relevant oncological target.…”