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Cited by 114Testicular diseases and treatmentsSperm and Testicular FunctionCancer Immunotherapy and Biomarkers

Specific Immune Cell and Cytokine Characteristics of Human Testicular Germ Cell Neoplasia

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Klein, Britta, Haggeney, Thomas, Fietz, Daniela, Indumathy, Sivanjah, Loveland, Kate L., Hedger, Mark, Kliesch, Sabine, Weidner, Wolfgang +2 more·2016·Human Reproduction
DOI 10.1093/humrep/dew211
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Abstract

STUDY QUESTION: Which immune cells and cytokine profiles are characteristic for testicular germ cell neoplasia and what consequences does this have for the understanding of the related testicular immunopathology? SUMMARY ANSWER: The unique immune environment of testicular germ cell neoplasia comprises B cells and dendritic cells as well as high transcript levels of IL-6 and other B cell supporting or T helper cell type 1 (Th1)-driven cytokines and thus differs profoundly from normal testis or inflammatory lesions associated with hypospermatogenesis. WHAT IS KNOWN ALREADY: T cells are known to be the major component of inflammatory infiltrates associated with either hypospermatogenesis or testicular cancer. It has previously been reported that B cells are only involved within infiltrates of seminoma samples, but this has not been investigated further. STUDY DESIGN, SIZE, DURATION: Immunohistochemical characterisation (IHC) of infiltrating immune cells and RT-qPCR-based analysis of corresponding cytokine microenvironments was performed on different testicular pathologies. Testicular biopsies, obtained from men undergoing andrological work-up of infertility or taken during surgery for testicular cancer, were used in this study. Samples were grouped as follows: (i) normal spermatogenesis (n = 18), (ii) hypospermatogenesis associated with lymphocytic infiltrates (n = 10), (iii) samples showing neoplasia [germ cell neoplasia in situ (GCNIS, n = 26) and seminoma, n = 18]. PARTICIPANTS/MATERIALS, SETTING, METHODS: IHC was performed using antibodies against T cells (CD3+), B cells (CD20cy+), dendritic cells (CD11c+), macrophages (CD68+) and mast cells (mast cell tryptase+). Degree and compartmental localisation of immune cells throughout all groups analysed was evaluated semi-quantitatively. RT-qPCR on RNA extracted from cryo-preserved tissue samples was performed to analyse mRNA cytokine expression, specifically levels of IL-1β, IL-6, IL-17a, tumour necrosis factor (TNF)-α (pro-inflammatory), IL-10, transforming growth factor (TGF)-β1 (anti-inflammatory), IL-2, IL-12a, IL-12b, interferon (IFN)-γ (Th1-driven), IL-4, IL-5, IL-13, IL-23a (Th2-driven), CXCL-13, CXCL-10 and CCL-5 (chemokines). MAIN RESULTS AND THE ROLE OF CHANCE: This is the first study showing a direct linkage between the distribution pattern of immune cells in hypospermatogenesis versus testicular cancer and analysis of a wide range of 17 related cyto- and chemokines. A fundamental difference between testicular inflammation patterns associated with different testicular inflammatory conditions either containing or lacking neoplastic cells was demonstrated. In hypospermatogenesis, T cells were detected, whereas B cells and dendritic cells were almost absent. Within GCNIS and seminoma, in addition to T cells, high numbers of dendritic cells and B cells were found, the latter additionally organised in cell clusters, whereas mast cells were absent. Transcripts encoding pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), anti-inflammatory cytokines (TGF-β1), Th1-driven cytokines (IL-2 and IFN-γ) as well as chemokines (CXCL-13, CXCL-10 and CCL-5) were all significantly increased in testicular germ cell neoplasia (P ≤ 0.01), suggesting the presence of a pro-tumorigenic environment. In contrast, Th2-related cytokines (IL-5, IL-13 and IL-23a) characterised the environment within samples showing normal spermatogenesis as well as hypospermatogenesis. One of the most important outcomes is the pivotal role of IL-6 in testicular cancer that opens potential novel diagnostic and/or immune-therapeutic perspective for testis cancer. LIMITATIONS, REASONS FOR CAUTION: Testicular tissue composed of immune cells as well as other somatic cells and germ cells does not allow identification of specific cytokine sources or single cell types, being responsible for establishing the overall cytokine environment. In this study, laser-assisted microdissection did not reach the required efficiency for RT-qPCR analyses. Therefore, in vitro models would be suggested for addressing the above-mentioned issue. Conclusions about cytokine levels in testes with GCNIS are based on a small number of samples. WIDER IMPLICATIONS OF THE FINDINGS: The unique B cell presence and the significantly increased expression level of IL-6 in testicular germ cell neoplasia (P < 0.001) strengthen its special role in this disease. In line with current knowledge on other types of cancer, these results underline the relevance of further investigating the potential of IL-6 as early biomarker and target for therapeutic intervention in testicular germ cell neoplasia. STUDY FUNDING/COMPETING INTERESTS: This study (and B.K. in person) was supported by the Deutsche Forschungsgemeinschaft (DFG) as part of the International Research Training Group between Justus Liebig University of Giessen and Monash University, Melbourne (GRK 1871/1) on 'Molecular pathogenesis on male reproductive disorders'. T.H., H.-C.S. and M.B. we

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  • In patients with testicular tumors, B-cells and dendritic cells are abundant in TME, while T cells are present in both malignant and normal tissue.

    “In patients with testicular tumors, B-cells and dendritic cells are abundant in TME, while T cells are present in both malignant and normal tissue.”

    From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [20]

  • Increased transcript levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, anti-inflammatory TGF-β1, Th1-driven IL-2 and IFN-γ, and chemokines CXCL-13, CXCL-10, CCL-5 are found in patients with testicular tumors.

    “In addition to infiltrating immune cells, increased transcript levels of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, anti-inflammatory cytokines (TGF-β1), Th1-driven cytokines (IL-2 and IFN-γ) and chemokines (CXCL-13, CXCL-10 and CCL-5) are found in patients with testicular tumors [20].”

    From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [20]

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  1. [10]10. Dinarello CA. Pro-inflammatory cytokines. Chest 2000;118:503-508.
  2. [27]27. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumour microenvironment. J Immun Res 2014;2014:149185.
  3. [29]29. Marconi M, Keudel A, Diemer T, Bergmann M, Steger K, Schuppe H-C, Weidner W. Combined trifocal-and micro-TESE is the best technique for testicular sperm retrieval in 'low chance' non-obstructive azoosper- mia. Eur Urol 2012;62:713-19.

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Authors
Klein, B., Haggeney, T., Fietz, D., Indumathy, S., Loveland, K. L., Hedger, M., Kliesch, S., Weidner, W., Bergmann, M., & Schuppe, H.-C.
Affiliations
  • Justus-Liebig-Universität Gießen (DE)
  • Hudson Institute of Medical Research (AU)
  • University of Münster (DE)
Corresponding author
Klein, Britta
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2016-09-08
Volume
31
Issue
10
Pages
2192-2202
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/dew211
OpenAlex
W2511420028
Cited by
114
References
50
Citations by year
2026: 10 · 2025: 17 · 2024: 13 · 2023: 18 · 2022: 14 · 2021: 10 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 1
FWCI
7.75
Type
journal article
Language
en
Open access
Locations
  • Human Reproduction (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (GRK 1871, GRK 1871/1, 1871/1)
  • Monash University (1871/1, GRK 1871/1, GRK 1871)
  • State Government of Victoria
  • National Health and Medical Research Council (1081987, 1079646)
Topics
  • Health Sciences › Medicine › Surgery › Testicular diseases and treatments
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
germ cell neoplasia in situ, seminoma, immune cell infiltration, B cells, dendritic cells, macrophages, mast cells, cytokine expression, Th1 cytokines, interleukin-6, IL-10, IL-17, IL-23, IL-12, IL-4, IL-5, IL-13, IL-1β, TNF-α, TGF-β1, hypospermatogenesis
MeSH terms
Adult, B-Lymphocytes, Dendritic Cells, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal, Testicular Neoplasms, Testis, Cytokines, Th1 Cells, Young Adult

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