Abstract
Purpose
An increasing infiltration of FoxP3-positive T-regs is associated with a higher grade of cervical intraepithelial neoplasia. The T-reg-recruiting chemokine CCL22 is expressed in various tumour entities. Aim of our study was to investigate the role of CCL22 in the progression and regression of cervical intraepithelial neoplasias, especially in patients with intermediate cervical intraepithelial neoplasias (CIN II). Furthermore, our aim was to characterize the CCL22-producing cells and explore the role of innate immunity in the process of cells recruitment.
Methods
CCL22 expression was analyzed immunohistochemically in 169 patient samples. The immunoreactive score as well as the median numbers of positive cells were calculated in each slide and correlated with the histological CIN grade and FoxP3 expression. Additionally, CD68/CCL22 as well as CD68/PPARγ and CD68/FoxP3 expression were examined by double immunofluorescence. Statistical analysis was performed by SPSS 26.
Results
A significantly higher expression of epithelial CCL22 in CIN II with progression in comparison to CIN II with regression (p = 0.006) could be detected. CCL22 was correlated with FoxP3 (Spearman’s Rho: 0.308; p < 0.01). In 88%, CCL22-positive cells were positive for CD68, and 71% of CD68-positive macrophages expressed PPARγ. Colocalization of CD68 and FoxP3 was detected in 12%.
Conclusion
We could demonstrate that increased expression of CCL22, mainly produced by macrophages, correlates with elevated potential of malignancy. CCL22 expression could act as a predictor for regression and progression in cervical intraepithelial neoplasia, and it may help in the decision process regarding surgical treatment versus watchful waiting strategy in order to prevent conisation-associated risks. Furthermore, our findings support the potential of CCL22-producing cells as a target for immune therapy in cervical cancer patients.
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Data availability
The datasets generated and analysed during the current study are available from the correspondent author on reasonable request.
Abbreviations
- CCL:
-
C–C-chemokine ligand
- CCR:
-
C–C-chemokine receptor
- CD:
-
Cluster differentiation
- CIN:
-
Cervical intraepithelial neoplasia
- CTLA4:
-
Cytotoxic T-lymphocyte-associated protein 4
- Cy-2, Cy-3:
-
Cyanine-2,-3
- Fig:
-
Figure
- FoxP3:
-
Forkhead box protein 3
- GITR:
-
Glucocorticoid-induced TNF-Receptor
- GM-CSF:
-
Granulocyte–macrophage colony-stimulating factor
- HB-EGF:
-
Heparin-binding epidermal growth factor like growth factor
- HER2:
-
Human epidermal growth factor receptor 2
- HLA-DR:
-
Human leukocyte antigene
- HSIL:
-
High grade squamous intraepithelial lesion
- IL:
-
Interleukine
- IRS-Score:
-
Immunoreactive score
- LAG3:
-
Lymphocyte activating 3
- LEEP/LEETZ:
-
Loop electrosurgical procedure/large loop excision of the transformation zone
- LSIL:
-
Low grade squamous intraepithelial lesion
- PBS:
-
Phosphate buffered saline
- PD-L1:
-
Programmed death ligand 1
- PGE-2:
-
Prostaglandine E
- PPAR:
-
Peroxisome-proliferator-activated receptor
- SKP2:
-
S-Phase kinase associated protein 2
- Smad2/3:
-
MAD (mothers against decapentaplegic)/ sma (small body size)
- TCR:
-
T-cell receptor
- TGF:
-
Transforming growth factor
- TLR8:
-
Toll-like receptor 8
- Treg:
-
Regulatory T-cell
- VEGF:
-
Vascular endothelial growth factor
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Acknowledgements
We thank Christina Kuhn, Andrea Sendelhofert, and Anja Heier for their excellent technical assistance.
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This study was funded by the Friedrich-Baur Foundation, LMU Munich.
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by NK, AV, TK and LH. The first draft of the manuscript was written by NK, AV and TK and all authors commented on previous versions of the manuscript. All authors analysed and interpreted the data and read and approved the final manuscript.
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Sven Mahner—Research funding, advisory board, honorary or travel expenses: AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro.
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Vattai, A., Kremer, N., Meister, S. et al. Increase of the T-reg-recruiting chemokine CCL22 expression in a progressive course of cervical dysplasia. J Cancer Res Clin Oncol 149, 6613–6623 (2023). https://doi.org/10.1007/s00432-023-04638-w
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DOI: https://doi.org/10.1007/s00432-023-04638-w