Sunitinib improves tumor microenvironment and augments the T cell infiltration and the effect of immunotherapy by DR-5

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461176
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Okazaki Tatsuma 東北大学, 大学病院, 講師 (40396479)
• Co-Investigator(Renkei-kenkyūsha): Yagita Hideo 順天堂大学, 医学部, 准教授 (30182306)
• Research Collaborator: Kobayashi Makoto 東北大学病院, 呼吸器内科 ; Tamai Tokiwa 東北大学病院, 呼吸器内科 ; Nihei Mayumi 東北大学病院, 呼吸器内科 ; Tsukita Yoko 東北大学病院, 呼吸器内科 ; Komatsu Riyo 東北大学病院, 呼吸器内科
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 腫瘍微小環境 / 血管新生 / リンパ管新生 / 腫瘍免疫

Outline of Final Research Achievements

VEGFR-2 in angiogenesis and VEGFR-3 in lymphangiogenesis are the key players. An anti-DR-5 Ab, the apoptosis inducing antibody, has antitumor effects. Here, we combined anti-DR-5 Ab with VEGFR1-3 inhibitor sunitinib as anti-angiogenic and lymphangiogenic therapies. Mice were injected with 4T1 cells into the footpad and treated with sunitinib and/or anti-DR-5 Ab. The tumors and popliteal lymph nodes were isolated. The growth rate of 4T1 or CT26 tumors was measured. Sunitinib decreased the blood vessel and hypoxic area densities in the tumors, suggesting blood vessel normalization. Sunitinib decreased the amount of tumor injected evans blue and hyaluronic acid in tumors, suggesting better lymphatic flow. The combination increased the ratio of activated dendritic cells and CD8+ T cells in lymph nodes and the numbers of CD8+ and effector CD4+ T cells in tumors compared to controls. The combination decreased the tumor growth rate compared to each mono-therapy.

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