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Prof. Dr. Astrid Schmieder

THE ROLE OF TUMOR-ASSOCIATED MACROPHAGES IN MELANOMA

Macrophages are a heterogeneous population of immune cells that function both in innate and adaptive immunity. As highly plastic cells they exhibit a wide spectrum of functional phenotypes in response to environmental stimuli and mediate their effects not only through phagocytosis but also through the production of different cytokines and chemokines. Macrophages are strongly involved in many chronic inflammatory diseases and also in tumor growth. During tumor progression, circulating monocytes and macrophages are actively recruited into tumors and are educated to promote tumor growth, angiogenesis, metastasis and immunosuppression. In many tumor entities, including malignant melanoma, a high infiltration of Tumor-associated macrophages (TAM) correlates with a poor clinical outcome. Therefore, TAMs are potential therapeutic targets for adjuvant tumor therapies.

Dying tumor cells induce the migration of P2Y12+ macrophages. B16F1 melanoma cells were treated with 2 μg/ml puromycin (puro) for 24 hours to trigger cell death. 10 μM PSB0739 or 10 μM of cangrelor were added to the puro-treated B16F1 cells. Untreated B16F1 cells were used as control. Transgenic RAW264.7 cells were sown in transwell inserts and given to the B16F1 cells. After 6 h, the migrated cells were fixed with methanol and dyed with crystal violet. Microscopic images of the migrated cells on the underside of the transwell membrane are shown.

The overall goals of our research are to further determine the function of TAM and the CD163+ TAM subpopulation both in vitro and in vivo in our melanoma mouse and in vitro models. In recent years, our group has mainly focused on the identification of new TAM targets and their molecular and functional characterization. For example, we identified Ms4a8a, Stabilin-1, Slamf9, Lyve-1, P2Y12+ TAM in melanoma. As CD163 and many of our previously identified TAM markers can be induced in vitro in peripheral blood monocytes (pBMs) by stimulation with glucocorticoids (Dollt et al, Kloss et al) we also study the relevance of the glucocorticoid receptor (GR) for TAM differentiation in melanoma. Further, we investigate the role of TAM on the therapeutic response to immune checkpoint inhibitors (ICIs) since TAM might diminish their efficacy due to their strong immunosuppressive capacity in the tumor stroma.


P2Y12 is expressed by tumor-associated macrophages in melanoma. Microscopic images of immunohistochemical and immunofluorescence stainings of human melanoma with anti-P2Y12, anti-CD68 and anti-CD163 antibodies are shown as well as P2Y12 mRNA in situ hybridization.

Publications

Kloss, L., Dollt, C., Schledzewski, K., Krewer, A., Melchers, S., Manta, C., Sticht, C., de la Torre, C., Utikal, J., Umansky, V, Schmieder, A. (2019). ADP secreted by dying melanoma cells mediates chemotaxis and chemokine secretion of macrophages via the purinergic receptor P2Y12. Cell Death Dis. 2019 Oct 7;10(10):760.

Dollt C*, Michel J*, Kloss L*, Melchers S, Schledzewski K, Becker K, Sauer A, Krewer A, Koll F, Schmieder A. 2018. The novel immunoglobulin super family receptor SLAMF9 identified in TAM of murine and human melanoma influences pro-inflammatory cytokine secretion and migration. Cell Death Dis. 2018 Sep 19;9(10):939. doi: 10.1038/s41419-018-1011-1

Dollt, C., Becker, K., Michel, J., Melchers, S., Weis, C. A., Schledzewski, K., Krewer, A., Kloss, L., Gebhardt, C., Utikal, J., and Schmieder, A. (2017). The shedded ectodomain of Lyve-1 expressed on M2-like tumor-associated macrophages inhibits melanoma cell proliferation. Oncotarget, 103682-103692.

Schmieder, A., Schledzewski, K., Michel, J., Tuckermann, J. P., Tome, L., Sticht, C., Gkaniatsou, C., Nicolay, J. P., Demory, A., Faulhaber, J., et al. (2011b). Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2-like tumor-associated macrophages expressing the novel CD20 homolog MS4A8A. International journal of cancer, 122-132.

Michel, J., Schönhaar, K., Schledzewski, K., Gkaniatsou, C., Sticht, C., Kellert, B., Lasitschka, F., Geraud, C., Goerdt, S. & Schmieder, A. (2013). Identification of the novel differentiation marker MS4A8B and its murine homolog MS4A8A in colonic epithelial cells lost during neoplastic transformation in human colon. Cell Death Dis 4, e469.

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