Angiogenic inhibitor pre‐administration improves the therapeutic effects of immunotherapy

Author:

Sato Mineyoshi12,Maishi Nako1,Hida Yasuhiro34,Yanagawa‐Matsuda Aya1,Alam Mohammad Towfik1,Sakakibara‐Konishi Jun2ORCID,Nam Jin‐Min5,Onodera Yasuhito5,Konno Satoshi2,Hida Kyoko1ORCID

Affiliation:

1. Vascular Biology and Molecular Pathology Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University Sapporo Japan

2. Department of Respiratory Medicine, Faculty of Medicine Hokkaido University Sapporo Japan

3. Department of Cardiovascular and Thoracic Surgery, Faculty of Medicine Hokkaido University Sapporo Japan

4. Advanced Robotic and Endoscopic Surgery, School of Medicine Fujita Health University Toyoake Japan

5. Global Center for Biomedical Science and Engineering (GCB), Faculty of Medicine Hokkaido University Sapporo Japan

Abstract

AbstractIn lung cancer, immune checkpoint inhibitors (ICIs) are often inadequate for tumor growth inhibition. Angiogenic inhibitors (AIs) are required to normalize tumor vasculature for improved immune cell infiltration. However, in clinical practice, ICIs and cytotoxic antineoplastic agents are simultaneously administered with an AI when tumor vessels are abnormal. Therefore, we examined the effects of pre‐administering an AI for lung cancer immunotherapy in a mouse lung cancer model. Using DC101, an anti‐vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, a murine subcutaneous Lewis lung cancer (LLC) model was used to determine the timing of vascular normalization. Microvessel density (MVD), pericyte coverage, tissue hypoxia, and CD8‐positive cell infiltration were analyzed. The effects of an ICI and paclitaxel after DC101 pre‐administration were investigated. On Day 3, increased pericyte coverage and alleviated tumor hypoxia represented the highest vascular normalization. CD8+ T‐cell infiltration was also highest on Day 3. When combined with an ICI, DC101 pre‐administration significantly reduced PD‐L1 expression. When combined with an ICI and paclitaxel, only DC101 pre‐administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre‐administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration.

Funder

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Publisher

Wiley

Subject

Cancer Research,Radiology, Nuclear Medicine and imaging,Oncology

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