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Cancer Res. 2018 Aug 1;78(15):4270-4281. doi: 10.1158/0008-5472.CAN-17-2176. Epub 2018 May 18.

Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer.

Author information

1
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
2
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
3
Cologne Interventional Immunology, University Hospital Cologne, Cologne, Germany.
4
Department of Medical Oncology, Dana-Faber Cancer Institute, Boston, Massachusetts.
5
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; US Institute for Pathology, University Hospital Cologne, Cologne, Germany.
6
Institute for Pathology, University Hospital Cologne, Cologne, Germany.
7
Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany.
8
German Hodgkin Study Group, Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
9
Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany.
10
Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne; University Hospital Bonn, Bonn, Germany.
11
Cologne Excellence Cluster in Cellular Stress Responses and Aging-associated Disorders (CECAD), Cologne, Germany.
12
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany. roland.ullrich@uk-koeln.de.

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. Cancer Res; 78(15); 4270-81. ©2018 AACR.

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