In patients with NSCLC, increased expression of IL-10 in the region surrounding the tumor positively correlated with tumor diameter. In the subset of patients with adenocarcinoma (ADC), tumor-infiltrating Foxp3+ Treg and tumor cells expressed IL-10R, which inversely correlated with PD-L1/PD-1 expression; in an ADC cell line, IL-10 downregulated PD-1, PD-L1, and FAS/FASL, indicating that IL-10/IL-10R expression may be linked to PD-1/PD-L1 blockade resistance. Meanwhile, in patients with squamous cell carcinoma, IL-10R directly correlated with PD-L1 expression.
BACKGROUND: Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape. METHODS: Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer. RESULTS: Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3+ T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis. CONCLUSIONS: These new findings suggest that IL-10 counteracts IFN-gamma effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.British Journal of Cancer advance online publication 10 October 2017 doi:10.1038/bjc.2017.336 www.bjcancer.com.
Author Info: (1) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlange
Author Info: (1) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (2) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (3) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (4) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (5) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (6) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (7) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (8) Institute of Pathology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Krankenhausstrabetae 8-10, Erlangen 91054, Germany. (9) Institute of Pathology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Krankenhausstrabetae 8-10, Erlangen 91054, Germany. (10) Department of Thoracic Surgery, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Krankenhausstrabetae 12, Erlangen 91054, Germany. (11) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany. (12) Institute of Pathology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Krankenhausstrabetae 8-10, Erlangen 91054, Germany. (13) Department of Thoracic Surgery, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Krankenhausstrabetae 12, Erlangen 91054, Germany. (14) Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU), Hartmannstrabetae 14, Erlangen 91052, Germany.
