Anti-angiogenic effects of PD-L1 blockade as a potential predictive biomarker

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15488
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: The University of Tokushima
• Principal Investigator: MITSUHASHI Atsushi 徳島大学, 大学院医歯薬学研究部(医学域), 特任助教 (00833732)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 免疫チェックポイント阻害薬 / 血管新生 / CXCL10/11 / がん

Outline of Final Research Achievements

PD-L1 blockade has been approved for various cancers as imune checkpoint inhibitor (ICI). However, the underlying anti-tumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We found that PD-L1 blockade inhibited tumor angiogenesis and induces hypoxia only in ICI-sensitive mouse model. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, IFN-γ inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing antibody or CXCL11-silencing in tumor cells inhibited the anti-angiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung adenocarcinoma patients receiving anti-PD-1 antibody, the concentration of CXCL10/11 correlated with the clinical outcome. Our results demonstrated the anti-angiogenic function of PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential predictive biomarker of therapeutic sensitivity.

Free Research Field

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Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害薬は進行がん治療において中心的な役割を担っており、その治療効果予測因子を同定することでがん免疫療法の分野における個別化医療の進展が見込まれる。さらに、腫瘍細胞由来ケモカイン発現を中心とした治療耐性化メカニズムの同定を目的としており、耐性克服に向けた新規複合がん免疫療法の開発が期待される。また、腫瘍免疫と血管新生の関連性における新たな知見が認められ、学術的な進展にも寄与すると考える。