The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma

Abstract

Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures (n = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.

Artificial Neural Network Analysis of Gene Expression Data Predicted Non-Hodgkin Lymphoma Subtypes with High Accuracy

“…Elevated CRP is associated with poor prognosis in follicular lymphoma [27]. ARG1 expression defines immunosuppressive subsets of tumor-associated macrophages [28], and macrophages contribute to follicular lymphoma pathogenesis [29]. Interestingly, CD19 was the least important gene, which makes pathological sense as CD19 is a pan B-cell marker common to all the non-Hodgkin lymphoma (NHL) subtypes.…”

“…However, there is information regarding the most relevant genes. For example, LCE2B has been related to laryngeal squamous cell carcinoma [30]; and macrophages express ARG1 [28], which affect the follicular lymphoma pathogenesis [29], and other lymphomas such as Hodgkin lymphoma [31]. The multilayer perceptron analysis also predicted each subtype individually, with even higher accuracy, and the predictive genes were highlighted.…”

Safety of Immune Checkpoint Inhibitors in Elderly Patients: An Observational Study

“…Immune checkpoint inhibitors (ICIs) are the most substantial novelty of the last years, with wide applicability to both solid and non-solid oncological pathologies, leading to a satisfactory performance in outcome and tolerability. While in hematological pathologies PD-L1 and other factors have prognostic value, in solid malignancies we currently stratify patients by clinical characteristics such as age and comorbidities [6,7]. As the number of elderly treated with ICIs is steadily increasing, data on the outcome and toxicity profile in this sub-population appear critical.…”

CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells

“…However, cytokines known to induce the expression of CD163, such as IL-4, -13, and -10 [ 74 ], were not detected in AML CM ( Table S3 ). Alternatively, we hypothesized that it may depend on CSF1/CSF1R pathway activation, as in solid cancers [ 15 ] and lymphoma [ 27 , 28 ], which was confirmed by the abrogation of CD163 expression induced by AML CM supplemented with GW2580 or PLX3397 ( Figure 1 D).…”

“…The colony-stimulating factor-1 (CSF-1, also called M-CSF), which controls the survival, proliferation, differentiation, and polarization of MΦs by binding to its receptor, the CSF1R, is a promising therapeutic target in aggressive tumors and possibly in AML [ 24 ]. In multiple myeloma and mantle cell lymphoma, the inhibition of CSF1R can reprogram TAMs and reverse drug-resistance [ 25 , 26 , 27 , 28 ]. However, whether MΦs contribute to AML cell proliferation and/or survival in creating a protumorigenic niche associated with a protumoral MΦ orientation is not established.…”