Universität zu Köln

Feldkötter, Henning Dieter (2020). Effects of Genotoxic Stress on Macrophage Phenotype and Phagocytic Capacity. PhD thesis, Universität zu Köln.

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Abstract

The tumor microenvironment (TME) plays an important role in the genesis, progression and metastasis of malignancies. One of the key players in the TME are macrophages, referred to as tumor associated macrophages (TAMs). As macrophages are a very heterogenic group, their impact on disease progression and outcome varies strongly depending on the tumor entity. In most cases, TAMs are mainly associated with a poor prognosis in regard to tumor progression, therapy efficacy and disease relapse after treatment. Previous work from this laboratory could show that the application of genotoxic stress in form of a low dose treatment with a alkylating agent, Mafosfamide, induced an increase in the phagocytic capacity of macrophage cell lines as well as primary murine macrophages in vitro. This stimulatory effect was observed in an assay, which evaluated opsonised Fc-receptor (FcR) mediated phagocytosis, utilizing Phycoerythrin (PE) labelled latex beads as well as green fluorescent protein (GFP) labelled humanized lymphoma cells as engulfment targets. Opsonization was ensured through the addition of monoclonal therapeutic antibodies. In addition, it was observed that stressed macrophages undergo morphological changes, which upon treatment with Mafosfamide and Doxorubicin led to an increase in size as well as granularity, detected by confocal microscopy and flow cytometry. In this work, an increase in opsonised FcR-independent as well as nonopsonised phagocytic capacity of macrophages in vitro, caused by chemotherapy treatment, was observed. Interestingly, this effect was induced by either Mafosfamide or Doxorubicin treatment, mirroring the effect both chemotherapeutics had on opsonised FcR-dependent phagocytosis. Furthermore, for Mafosfamide this seemed to be caused by direct effects of the chemotherapeutic on the macrophages. The mechanism of action observed under Doxorubicin treatment differed from Mafosfamide in that it induced increased phagocytosis via both direct and indirect treatment.