Abstract
Purpose
Esophageal cancer (EC) is one of the most lethal gastrointestinal malignancies. Immunotherapy is a promising treatment modality for this disease. However, broader implementation of EC immunotherapy has been discouraged because of insufficient understanding of tumor interactions with the immune system. As with other malignancies, the current research on EC focuses on deciphering the immune cell signatures within the tumor microenvironment. However, the disease-elicited immune cell profiles in the paratumoral compartments are largely unknown.
Methods
We examined the immune cell signatures in 62 tissue samples from 16 EC patients in different esophageal tissue compartments: tumor tissue, peritumoral tissue, healthy esophageal tissue, and adjacent lymph nodes. We analyzed the proportions and distribution patterns of NK cells and CD4+ and CD8+ T cells as well as their death receptor (FasR, FasR/DR3)-expressing subpopulations. The analyzed data were then compared and correlated with the patients' clinicopathological data.
Results
We found that the FasR+ NK cells, CD4+ and CD8+ T cells infiltrated lymph nodes at the lowest levels and that the FasR+DR3+ CD4+ T cells were enhanced in tumors. The comparisons with the clinicopathological data revealed a major impact of active smoking on the reduction in paratumoral NK cells and the upregulation of FasR in tumor-infiltrating NK and CD8+ T cells. The lymph node metastatic stage, tumor stage, and Mandard grade correlated with the compartmental proportions of the evaluated immune cells.
Conclusion
The novel association of the disease state with tumoral and paratumoral immune cell signatures suggests new possibilities for personalized immunotherapy for EC patients.
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Acknowledgements
We thank the clinical research staff, professional laboratory staff and technicians for their assistance and Michal Rataj for assistance with the flow cytometry experiments. We also thank Prof. Ilja Striz and Dr. Alasdair M. Gilfillan for their critical review of the manuscript.
Funding
Research in the authors’ laboratories was supported by funding from the Charles University—project GA UK No. 364218, PRIMUS/MED/12, by funding from the Ministry of Health, Czech Republic—project AZV 16-28135A and the conceptual development fund of research organization University Hospital Motol, Prague, Czech Republic 00064203.
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J. Bartunkova is a part-time employee and a minority shareholder of Sotio, a.s., a biotech company developing cell-based immunotherapy. Z. Strizova, M. Snajdauf, D. Stakheev, P. Taborska, J. Vachtenheim Jr, J. Biskup, R. Lischke, and D. Smrz declare no conflict of interest.
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This study was approved by the Ethics committee for multicentric studies and evaluation of the Faculty Hospital Motol, Prague, Czech Republic. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Zuzana Strizova and Martin Snajdauf are co-first authors.
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Strizova, Z., Snajdauf, M., Stakheev, D. et al. The paratumoral immune cell signature reveals the potential for the implementation of immunotherapy in esophageal carcinoma patients. J Cancer Res Clin Oncol 146, 1979–1992 (2020). https://doi.org/10.1007/s00432-020-03258-y
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DOI: https://doi.org/10.1007/s00432-020-03258-y