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Original Article

Tumor necrosis factor receptor superfamily

member 9 is upregulated in the endothelium

and tumor cells in melanoma brain metastasis

Patrick N. Harter 1,2,3 , Anna‑Eva Blank , Benjamin Weide , Rudi Beschorner , Simon Bernatz , Peter Baumgarten ,
6
1
1,4
5
1,7
Anne K. Braczynski , Elke Hattingen , Michael W. Ronellenfitsch , Herbert Schwarz , Michel Mittelbronn 1,2,3
10
9
8
1
1 Institute of Neurology (Edinger Institute), Goethe University, 60528 Frankfurt, Germany.
2 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
3 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4 Department of Neuropediatrics, University of Frankfurt, 60590 Frankfurt, Germany.
5 Department of Dermatology, Eberhardt‑Karls University, 72076 Tuebingen, Germany.

6 Department of Neuropathology, Institute of Pathology and Neuropathology, Eberhardt‑Karls University, 72076 Tuebingen, Germany.
7 Department of Neurosurgery, Goethe University, 60528 Frankfurt, Germany.
8 Department of Neuroradiology, University of Frankfurt am Main, 60258 Frankfurt, Germany.
9 Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, 60258 Frankfurt, Germany.
10 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
ABSTRA CT
Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9) is mainly considered to be a co‑stimulatory
activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches
targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several
severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in
primary central nervous system (CNS) tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to
address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with
a prominent tropism to the CNS. Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry
for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number
of tumor spots, and BRAF V600E expression status. Results: Tumor necrosis factor receptor superfamily member 9 was frequently
expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of
larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or
other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells
with increasing distance from blood vessels, an observation that might be linked to hypoxia‑driven TNFRSF9 expression in tumor cells.
Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic
pool, and therefore further careful (re‑) assessment of potential TNFRSF9 functions in cell types other than hematopoietic cells is needed.
Furthermore, the hypothesis of hypoxia‑driven TNFRSF9 expression in brain metastasis melanoma cells requires further functional testing.
Key words: 4‑1BB, brain metastasis, CD137, melanoma, tumor necrosis factor receptor superfamily member 9

INTRODUCTION superfamily member 9 (TNFRSF9) (also known as
CD137 or 4‑1BB) is usually expressed upon cellular
The cytokine receptor tumor necrosis factor receptor activation and acts as a co‑stimulatory and the
pro‑survival molecule in different cellular subsets of the
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Quick Response Code: lymphoid and myeloid lineage. Hematopoietic cells
Website: which have been activated via TNFRSF9 stimulation
www.nnjournal.net
have shown an increased antitumor response in various
preclinical models. [2,3] This effect was mainly attributed
DOI:
10.4103/2347-8659.143670 to increased numbers of CD8‑positive cytotoxic
T‑cells as well as antigen‑specific memory T‑cells.

Corresponding Author: Prof. Michel Mittelbronn, Institute of Neurological (Edinger Institute), Goethe University,
Heinrich‑Hoffmann‑Strasse 7, 60528 Frankfurt (Main), Germany. E‑mail: michel.mittelbronn@kgu.de

Neuroimmunol Neuroinflammation | Volume 1 | Issue 3 | December 2014 135