Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors.

Autor: Knopf P; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Stowbur D; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany., Hoffmann SHL; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Hermann N; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Maurer A; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany., Bucher V; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Poxleitner M; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Tako B; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Sonanini D; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany., Krishnamachary B; Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Sinharay S; Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Rd, Houston, TX, 77054, USA., Fehrenbacher B; Department of Dermatology, Eberhard Karls University, Tübingen, Germany., Gonzalez-Menendez I; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany.; Institute of Pathology and Neuropathology, Department of Pathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany., Reckmann F; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany., Bomze D; Department of Dermatology, Tel-Aviv Medical Center, Tel-Aviv, Israel., Flatz L; Department of Dermatology, Eberhard Karls University, Tübingen, Germany., Kramer D; Interfaculty Institute of Biochemistry, Eberhard Karls University, Tübingen, Germany., Schaller M; Department of Dermatology, Eberhard Karls University, Tübingen, Germany., Forchhammer S; Department of Dermatology, Eberhard Karls University, Tübingen, Germany., Bhujwalla ZM; Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.; Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA., Quintanilla-Martinez L; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany.; Institute of Pathology and Neuropathology, Department of Pathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany., Schulze-Osthoff K; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany.; Interfaculty Institute of Biochemistry, Eberhard Karls University, Tübingen, Germany.; German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Pagel MD; Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Rd, Houston, TX, 77054, USA., Fransen MF; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, Netherlands., Röcken M; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany.; Department of Dermatology, Eberhard Karls University, Tübingen, Germany.; German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Martins AF; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany.; German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Pichler BJ; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany.; German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Ghoreschi K; Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany., Kneilling M; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany. manfred.kneilling@med.uni-tuebingen.de.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Röntgenweg 13, 72076, Tübingen, Germany. manfred.kneilling@med.uni-tuebingen.de.; Department of Dermatology, Eberhard Karls University, Tübingen, Germany. manfred.kneilling@med.uni-tuebingen.de.
Jazyk: angličtina
Zdroj: Molecular cancer [Mol Cancer] 2023 Dec 15; Vol. 22 (1), pp. 207. Date of Electronic Publication: 2023 Dec 15.
DOI: 10.1186/s12943-023-01900-0
Abstrakt: Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ -/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.
(© 2023. The Author(s).)
Databáze: MEDLINE
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