Research Papers:

Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma

Axel Lechner, Hans Schlößer, Sacha I. Rothschild, Martin Thelen, Sabrina Reuter, Peter Zentis, Alexander Shimabukuro-Vornhagen, Sebastian Theurich, Kerstin Wennhold, Maria Garcia-Marquez, Lars Tharun, Alexander Quaas, Astrid Schauss, Jörg Isensee, Tim Hucho, Christian Huebbers, Michael von Bergwelt-Baildon _ and Dirk Beutner

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Oncotarget. 2017; 8:44418-44433. https://doi.org/10.18632/oncotarget.17901

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Axel Lechner1,2,*, Hans Schlößer1,3,*, Sacha I. Rothschild1,4,*, Martin Thelen1, Sabrina Reuter1, Peter Zentis5, Alexander Shimabukuro-Vornhagen1,6, Sebastian Theurich1,6,7, Kerstin Wennhold1, Maria Garcia-Marquez1, Lars Tharun8, Alexander Quaas8, Astrid Schauss5, Jörg Isensee9, Tim Hucho9, Christian Huebbers10, Michael von Bergwelt-Baildon1,6,* and Dirk Beutner2,*

1Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

2Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany

3Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany

4University Hospital Basel, Department of Internal Medicine, Medical Oncology, Basel, Switzerland

5Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

6Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany

7Max-Planck-Institute for Metabolism Research, Cologne, Germany

8Institute of Pathology, University of Cologne, Cologne, Germany

9Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne, University of Cologne, Germany

10Jean-Uhrmacher Institute for Clinical ENT Research, University of Cologne, Cologne, Germany

*These authors contributed equally to this work

Correspondence to:

Michael von Bergwelt-Baildon, email: [email protected]

Keywords: squamous cell carcinoma, head and neck, microenvironment, T cells, immune checkpoint

Received: January 10, 2017     Accepted: April 25, 2017     Published: May 16, 2017


The composition of tumor-infiltrating lymphocytes (TIL) reflects biology and immunogenicity of cancer. Here, we characterize T-cell subsets and expression of immune checkpoint molecules in head and neck squamous cell carcinoma (HNSCC). We analyzed TIL subsets in primary tumors (n = 34), blood (peripheral blood mononuclear cells (PBMC); n = 34) and non-cancerous mucosa (n = 7) of 34 treatment-naïve HNSCC patients and PBMC of 15 healthy controls. Flow cytometry analyses revealed a highly variable T-cell infiltration mainly of an effector memory phenotype (CD45RA/CCR7). Naïve T cells (CD45RA+/CCR7+) were decreased in the microenvironment compared to PBMC of patients, while regulatory T cells (CD4+/CD25+/CD127low and CD4+/CD39+) were elevated. Furthermore, we performed digital image analyses of entire cross sections of HNSCC to define the ‘Immunoscore’ (CD3+ and CD8+ cell infiltration in tumor core and invasive margin) and quantified MHC class I expression on tumor cells by immunohistochemistry. Immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) were increased in TILs compared to peripheral T cells in flow-cytometric analysis. Human papillomavirus (HPV) positive tumors showed higher numbers of TILs, but a similar composition of T-cell subsets and checkpoint molecule expression compared to HPV negative tumors. Taken together, the tumor microenvironment of HNSCC is characterized by a strong infiltration of regulatory T cells and high checkpoint molecule expression on T-cell subsets. In view of increasingly used immunotherapies, a detailed knowledge of TILs and checkpoint molecule expression on TILs is of high translational relevance.

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