Meder, Lydia ORCID: 0000-0002-9547-5812, Schuldt, Philipp, Thelen, Martin ORCID: 0000-0002-2785-9726, Schmitt, Anna, Dietlein, Felix, Klein, Sebastian, Borchmann, Sven, Wennhold, Kerstin, Vlasic, Ignacija, Oberbeck, Sebastian, Riedel, Richard, Florin, Alexandra, Golfmann, Kristina, Schloesser, Hans A., Odenthal, Margarete, Buettner, Reinhard, Wolf, Juergen, Hallek, Michael, Herling, Marco, von Bergwelt-Baildon, Michael, Reinhardt, H. Christian and Ullrich, Roland T. (2018). Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer. Cancer Res., 78 (15). S. 4270 - 4282. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1-targeted therapy synergistically improves treatment outcome compared with anti-PD-L1 and anti-VEGF monotherapy. Mice treated with anti-PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double-positive exhausted T-cell phenotype. This exhausted T-cell phenotype upon PD-L1 blockade was abrogated by the addition of anti-VEGF-targeted treatment. We confirmed a similar TIM-3-positive T-cell phenotype in peripheral blood mononuclear cells of patients with SCLC with adaptive resistance to anti-PD-1 treatment. Mechanistically, we show that VEGFA enhances coexpression of the inhibitory receptor TIM-3 on T cells, indicating an immunosuppressive function of VEGF in patients with SCLC during anti-PD-1-targeted treatment. Our data strongly suggest that a combination of anti-VEGF and anti-PD-L1 therapies can be an effective treatment strategy in patients with SCLC. Significance: Combining VEGF and PD-L1 blockade could be of therapeutic benefit to patients with small cell lung cancer. (C) 2018 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Meder, LydiaUNSPECIFIEDorcid.org/0000-0002-9547-5812UNSPECIFIED
Schuldt, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, MartinUNSPECIFIEDorcid.org/0000-0002-2785-9726UNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borchmann, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wennhold, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vlasic, IgnacijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oberbeck, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golfmann, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schloesser, Hans A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bergwelt-Baildon, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-177125
DOI: 10.1158/0008-5472.CAN-17-2176
Journal or Publication Title: Cancer Res.
Volume: 78
Number: 15
Page Range: S. 4270 - 4282
Date: 2018
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ENDOTHELIAL GROWTH-FACTOR; TUMOR-ASSOCIATED MACROPHAGES; CD8(+) T-CELLS; ACQUIRED-RESISTANCE; IMMUNE SUPPRESSION; CARCINOMA PATIENTS; EXPRESSION; TIM-3; IMMUNOTHERAPY; MELANOMAMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17712

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