Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain

GND
1219598496
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Herrera-Rios, Dayana;
GND
115188734X
Affiliation
Division of Applied Bioinfomatics, German Cancer Research Center (DKFZ)
Mughal, Sadaf S.;
GND
1078509859
Affiliation
Medical Faculty, West German Cancer Center, Institute of Neuropathology, University Duisburg-Essen
Teuber-Hanselmann, Sarah;
GND
174037228
ORCID
0000-0003-0980-7444
Affiliation
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf
Pierscianek, Daniela;
GND
1161138153
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Sucker, Antje;
GND
1199288306
ORCID
0000-0003-3139-2118
LSF
60180
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Jansen, Philipp;
GND
136477984
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Schimming, Tobias;
GND
137117906
ORCID
0000-0001-9239-7014
LSF
54032
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Klode, Joachim;
GND
131341464
Affiliation
Department of Dermatology, Medical Faculty, Heinrich Heine University
Reifenberger, Julia;
GND
120103788
Affiliation
Medical Faculty, Institute of Neuropathology, Heinrich Heine University
Felsberg, Jörg;
GND
1204608865
ORCID
0000-0003-2558-5159
LSF
50603
Affiliation
Medical Faculty, West German Cancer Center, Institute of Neuropathology, University Duisburg-Essen
Keyvani, Kathy;
GND
1112102965
Affiliation
Division of Applied Bioinfomatics, German Cancer Research Center (DKFZ)
Brors, Benedikt;
GND
113528884
LSF
50510
Affiliation
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf
Sure, Ulrich;
GND
1082574740
Affiliation
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf
Reifenberger, Guido;
GND
11142576X
ORCID
0000-0003-3524-7858
LSF
50631
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Schadendorf, Dirk;
GND
1176221531
ORCID
0000-0001-6150-9570
LSF
53805
Affiliation
Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen
Helfrich, Iris

The manifestation of brain metastases in patients with advanced melanoma is a common event that limits patient's survival and quality of life. The immunosuppressive properties of the brain parenchyma are very different compared to the rest of the body, making it plausible that the current success of cancer immunotherapies is specifically limited here. In melanoma brain metastases, the reciprocal interplay between immunosuppressive mediators such as indoleamine 2, 3-dioxygenase (IDO) or programmed cell death-ligand 1 (PD-L1) in the context of neoplastic transformation are far from being understood. Therefore, we analyzed the immunoreactive infiltrate (CD45, CD3, CD8, Forkhead box P3 [FoxP3], CD11c, CD23, CD123, CD68, Allograft Inflammatory factor 1[AIF-1]) and PD-L1 with respect to IDO expression and localization in melanoma brain metastases but also in matched metastases at extracranial sites to correlate intra- and interpatient data with therapy response and survival. Comparative tissue analysis identified macrophages/microglia as the major source of IDO expression in melanoma brain metastases. In contrast to the tumor infiltrating lymphocytes, melanoma cells per se exhibited low IDO expression levels paralleled by cell surface presentation of PD-L1 in intracranial metastases. Absolute numbers and pattern of IDO-expressing cells in metastases of the brain correlated with recruitment and localization of CD8 + T cells, implicating dynamic impact on the regulation of T cell function in the brain parenchyma. However, paired analysis of matched intra- and extracranial metastases identified significantly lower fractions of cytotoxic CD8 + T cells in intracranial metastases while all other immune cell populations remain unchanged. In line with the already established clinical benefit for PD-L1 expression in extracranial melanoma metastases, Kaplan-Meier analyses correlated PD-L1 expression in brain metastases with favorable outcome in advanced melanoma patients undergoing immune checkpoint therapy. In summary, our data provide new insights into the landscape of immunosuppressive factors in melanoma brain metastases that may be useful in the implication of novel therapeutic strategies for patients undergoing cancer immunotherapy.

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Citation style:
Herrera-Rios, D., Mughal, S.S., Teuber-Hanselmann, S., Pierscianek, D., Sucker, A., Jansen, P., Schimming, T., Klode, J., Reifenberger, J., Felsberg, J., Keyvani, K., Brors, B., Sure, U., Reifenberger, G., Schadendorf, D., Helfrich, I., 2020. Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain. https://doi.org/10.3389/fimmu.2020.00120
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Copyright © 2020 Herrera-Rios, Mughal, Teuber-Hanselmann, Pierscianek, Sucker, Jansen, Schimming, Klode, Reifenberger, Felsberg, Keyvani, Brors, Sure, Reifenberger, Schadendorf and Helfrich.

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