A Boolean Model of the Formation of Tumour Associated Macrophages in anin-vitroModel of Chronic Lymphocytic Leukaemia

Abstract

The tumour microenvironment is the collection of cells in and surrounding cancer cells in a tumour including a variety of immune cells, especially neutrophils and monocyte-derived macrophages. In a tumour setting, macrophages encompass a spectrum between a tumour-suppressive (M1) or tumour-promoting (M2) state. The biology of macrophages found in tumours (Tumour Associated Macrophages) remains unclear, but understanding their impact on tumour progression is highly important. In this paper, we perform a comprehensive analysis of a macrophage polarization network, following two lines of enquiry: (i) we reconstruct the macrophage polarization network based on literature, extending it to include important stimuli in a tumour setting, and (ii) we build a dynamical model able to reproduce macrophage polarization in the presence of different stimuli, including the contact with cancer cells. Our simulations recapitulate the documented macrophage phenotypes and their dependencies on specific receptors and transcription factors, while also elucidating the formation of a special type of tumour associated macrophages in an in-vitro model of Chronic Lymphocytic Leukaemia. This model constitutes the first step towards elucidating the cross-talk between immune and cancer cells inside tumours, with the ultimate goal of identifying new therapeutic targets that could control the formation of tumour associated macrophages in patients.

An Agent-Based Model of Monocyte Differentiation into Tumour-Associated Macrophages in Chronic Lymphocytic Leukemia

“…One of the limitations in the study of TAMs is the difficulty in identifying them in bulk tumour samples, due to their close similarity with other macrophages that are also present in the TME. However, we showed that although NLCs and M2-type macrophages display a similar profile in the CLL microenvironment (6), some distinctions can be highlighted, such as high expression of the RAGE membrane receptor, the HIF1𝞪 and VEGF/EGF transcription factors in NLCs (7). Given the nurturing properties of NLCs in the CLL microenvironment, a high number of NLCs has been reported to lead to disease progression and shorter overall survival (8), (9).…”