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Makrophagen im Melanom – von molekularen Signalen zur therapeutischen Anwendung

Melanoma-associated macrophages—from molecular signals to therapeutic application

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Zusammenfassung

Hintergrund

Makrophagen sind ein wichtiger Bestandteil des angeborenen Immunsystems. Sie werden mit Mφ, MΦ oder MP abgekürzt. Die Bezeichnung stammt aus dem Griechischen: große Fresser, von griechisch μακρóς (makrós) = groß, φαγεῖν (phagein) = essen, weil sie Krankheitserreger verschlingen und verdauen. Tumorassoziierte Makrophagen (TAM) werden mit Arzneimittelresistenz bei Krebserkrankungen einschließlich Melanom in Verbindung gebracht, und ihre gezielte Bekämpfung könnte die Tumortherapie verbessern.

Zielsetzungen

In diesem Beitrag soll die Rolle von TAM bei Krebserkrankungen und insbesondere beim Melanom untersucht werden. Der Zusammenhang zwischen TAM und Therapieresistenz sowie ihre potenzielle Anwendung bei der Behandlung von Melanomen wird erörtert.

Materialien und Methoden

Es wurde eine Literaturrecherche in den Datenbanken PubMed und Google Scholar zu TAM und Melanom durchgeführt. Klinische Studien wurden über clinicaltrials.gov recherchiert und die grafischen Darstellungen mittels BioRender (BioRender, Toronto, Canada) erstellt.

Ergebnisse

Beim Melanom gehören Makrophagen zu den häufigsten Immunzellen in der Mikroumgebung des Tumors (TME). TAM werden mit einer schlechten Prognose und Resistenz in Verbindung gebracht. Sie sind an der Entstehung von Tumoren und der Entwicklung von Metastasen beteiligt. M2 ist der vorherrschende Typ von TAM, und die M2-Marker CD163 und CD204 sind ungünstige prognostische Biomarker. Therapeutische Ansätze zielen darauf ab, ihre Rekrutierung zu verringern, ihre Funktion zu modulieren oder sie umzuprogrammieren. Therapien mit chimären Antigenrezeptor(CAR)-M-Zellen und Nanopartikeln werden derzeit untersucht. Zu den Medikamenten, die für das Melanom getestet werden, gehören Inhibitoren des „signal transducer and activator of transcription 3“ (STAT3), Antagonisten des Makrophagen-Kolonie-stimulierenden Faktors (M-CSF), Interferone (IFN), Talimogene laherparepvec (TVEC), Histon-Deacetylase(HDAC)-Inhibitoren, Indolamin‑2,3‑Dioxygenase(IDO)-Inhibitoren, Kolonie-stimulierender Faktor-1-Rezeptor(CSF-1R)-Antagonisten, CD40-Agonisten, Arginase 1(ARG-1)-Inhibitoren und Phosphoinositid-3-Kinase γ(PI3K-γ)-Inhibitoren.

Schlussfolgerungen

TAM sind an der Resistenz gegen aktuelle Melanomtherapien beteiligt. Eine gegen sie gerichtete Therapie könnte zur Verringerung der Resistenzentwicklung und zur Verbesserung der Überlebensrate beitragen.

Abstract

Background

Macrophages are an important component of the innate immune system. They are abbreviated as Mφ, MΦ, or MP. The name is derived from Greek: large eaters, μακρóς (makrós) = large, φαγεῖν (phagein) = to eat, because they engulf and digest pathogens. Tumor-associated macrophages (TAMs) are associated with drug resistance in cancers, including melanoma, and targeting them may improve cancer treatment.

Objectives

The purpose of this article is to examine the role of TAMs in cancer, particularly in melanoma. The relationship between TAM and treatment resistance and their potential application in the treatment of melanoma are discussed.

Materials and methods

A literature search in PubMed and Google Scholar databases for TAM and melanoma was performed. Clinical trials were searched via clinicaltrials.gov and graphical representations were created using BioRender.

Results

In melanoma, macrophages are among the most abundant immune cells in the tumor microenvironment (TME). TAMs are associated with poor prognosis and resistance. They are involved in tumorigenesis and metastasis development. M2 is the predominant type of TAM and the M2 markers CD163 and CD204 are unfavorable prognostic biomarkers. Therapeutic approaches aim to decrease their recruitment, modulate their function, or reprogram them. Treatment using chimeric antigen receptor (CAR)-M cells and nanoparticles are currently being investigated. Drugs being tested for melanoma include signal transducer and activator of transcription 3 (STAT3) inhibitors, macrophage colony-stimulating factor (M-CSF) antagonists, interferons (IFN), talimogene laherparepvec (TVEC), histone deacetylase (HDAC) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, colony-stimulating factor 1 receptor (CSF-1R) antagonists, CD40 agonists, arginase 1 (ARG-1) inhibitors, and phosphoinositide 3‑kinase γ (PI3K-γ) inhibitors.

Conclusions

TAMs participate in developing resistance to current melanoma therapies. Treatment directed against them may help reduce the development of resistance and improve survival.

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Authors and Affiliations

  1. Universitätshautklinik, Universitätsklinikum Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Deutschland

    Eftychia Chatziioannou, Stephan Forchhammer & Tobias Sinnberg

  2. Klinik für Dermatologie, Venerologie und Allergologie, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Luisenstr. 2, 10117, Berlin, Deutschland

    Serra Atilla Aydin, Tobias Sinnberg &  Thomas Eigentler

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  1. Eftychia Chatziioannou
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  2. Serra Atilla Aydin
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  3. Stephan Forchhammer
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  4. Tobias Sinnberg
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  5. Thomas Eigentler
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Correspondence to Thomas Eigentler.

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Interessenkonflikt

E. Chatziioannou, S.A. Aydin, S. Forchhammer, T. Sinnberg und T. Eigentler geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Die Arbeit wurde unter Berücksichtigung der guten wissenschaftlichen Praxis erstellt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Die Autoren Eftychia Chatziioannou und Serra Atilla Aydin haben zu gleichen Teilen zum Manuskript beigetragen.

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Chatziioannou, E., Aydin, S.A., Forchhammer, S. et al. Makrophagen im Melanom – von molekularen Signalen zur therapeutischen Anwendung. Dermatologie 73, 915–928 (2022). https://doi.org/10.1007/s00105-022-05077-3

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