CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival

  • Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity. We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line. We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected. In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
Metadaten
Author:Pia Susan ZeinerORCiD, Jenny Zinke, Daniel Johannes Kowalewski, Simon Bernatz, Julia Frederike TichyGND, Michael Wilfried RonellenfitschORCiDGND, Frits Thorsen, Annemarie Berger, Marie-Thérèse ForsterORCiDGND, Arnaud Muller, Joachim Peter SteinbachORCiDGND, Rudi Beschorner, Jörg Wischhusen, Hans-Michael KvasnickaORCiD, Karl H. Plate, Stefan Stefanovic, Benjamin Weide, Michel Guy André Mittelbronn, Patrick Nikolaus HarterORCiDGND
URN:urn:nbn:de:hebis:30:3-464951
DOI:https://doi.org/10.1186/s40478-018-0521-5
ISSN:2051-5960
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29490700
Parent Title (English):Acta Neuropathologica Communications
Publisher:Biomed Central
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/03/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/05/22
Tag:Brain metastasis; CD74; HLA class II; HLA peptidome; Tumor infiltrating lymphocytes
Volume:6
Issue:1, Art. 18
Page Number:16
First Page:1
Last Page:16
Note:
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS-PPN:433882255
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0