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Molecular Diagnostics

T-regulatory cells predict clinical outcome in soft tissue sarcoma patients: a clinico-pathological study

Abstract

Background

Soft tissue sarcomas (STS) are generally considered non-immunogenic, although specific subtypes respond to immunotherapy. Antitumour response within the tumour microenvironment relies on a balance between inhibitory and activating signals for tumour-infiltrating lymphocytes (TILs). This study analysed TILs and immune checkpoint molecules in STS, and assessed their prognostic impact regarding local recurrence (LR), distant metastasis (DM), and overall survival (OS).

Methods

One-hundred and ninety-two surgically treated STS patients (median age: 63.5 years; 103 males [53.6%]) were retrospectively included. Tissue microarrays were constructed, immunohistochemistry for PD-1, PD-L1, FOXP3, CD3, CD4, and CD8 performed, and staining assessed with multispectral imaging. TIL phenotype abundance and immune checkpoint markers were correlated with clinical and outcome parameters (LR, DM, and OS).

Results

Significant differences between histology and all immune checkpoint markers except for FOXP3+ and CD3−PD-L1+ cell subpopulations were found. Higher levels of PD-L1, PD-1, and any TIL phenotype were found in myxofibrosarcoma as compared to leiomyosarcoma (all p < 0.05). The presence of regulatory T cells (Tregs) was associated with increased LR risk (p = 0.006), irrespective of margins. Other TILs or immune checkpoint markers had no significant impact on outcome parameters.

Conclusions

TIL and immune checkpoint marker levels are most abundant in myxofibrosarcoma. High Treg levels are independently associated with increased LR risk, irrespective of margins.

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Fig. 1: Multispectral images of two myxofibrosarcomas.
Fig. 2: Immune checkpoint markers and TIL phenotype abundance depending on histology.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Not applicable.

Funding

This study was funded by the “Verein für Krebskranke” (Cancer Patient Society). Moreover, the current study was supported by the K1 COMET Competence Center CBmed (Center for Biomarker Research in Medicine), which is funded by the Federal Ministry of Transport, Innovation and Technology (BMVIT), Land Steiermark (Department 12, Business and Innovation), the Federal Ministry of Science, Research and Economy (BMWFW), the Styrian Business Promotion Agency (SFG), and the Vienna Business Agency. The COMET programme is executed by the Austrian Research Promotion Agency (FFG). LH was supported by CBmed via the PhD programme Advanced Medical Biomarker Research (AMBRA). The funding sources had no impact on the design of the study, its conduction, analysis, presentation of results or interpretation.

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Authors

Contributions

JS, AL, and MAS were responsible for the study design. The literature search was performed by LH, MP, MT, BG, AG, MG, and AE-H. Figures were plotted by LH, BP, MAS, and PL-G. Data were ascertained by MAS, BG, MG, SS, LH, JR, MT, and PL-G. Tumour sample and TMA preparations were performed by IVAB, BL-A, MT, and BP. TMA analysis was performed by BP, LH, PL-G, and MT. LH, PL-G, AE-H, AL, JS, and MAS were responsible for data analysis. Data interpretation was performed by SS, IVAB, MB, MP, AG, CR, JR, JS, and MAS. MAS, LH, AL, PL-G, and JS wrote the primary draft of the manuscript. All authors were responsible for the setup, writing, and revision of the main manuscript.

Corresponding author

Correspondence to Joanna Szkandera.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The current study was approved by the institutional review board (Ethics Commission of the Medical University of Graz, Austria; IRB approval number: 29-205 ex 16/17) of the primary study centre. Tissue samples were only included if patients’ informed consent to have their material analysed for research purposes was available.

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As no directly patient-identifying information is provided in the current study, consent for publication was not obtained from participants.

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Smolle, M.A., Herbsthofer, L., Granegger, B. et al. T-regulatory cells predict clinical outcome in soft tissue sarcoma patients: a clinico-pathological study. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01456-0

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