Increased vessel perfusion predicts the efficacy of immune checkpoint blockade
Xichen Zheng, … , Qingyu Wu, Yuhui Huang
Xichen Zheng, … , Qingyu Wu, Yuhui Huang
Published May 1, 2018; First published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2104-2115. https://doi.org/10.1172/JCI96582.
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Categories: Research Article Immunology Vascular biology

Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

Abstract

Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti–cytotoxic T lymphocyte–associated protein 4 or anti–programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.

Authors

Xichen Zheng, Zhaoxu Fang, Xiaomei Liu, Shengming Deng, Pei Zhou, Xuexiang Wang, Chenglin Zhang, Rongping Yin, Haitian Hu, Xiaolan Chen, Yijie Han, Yun Zhao, Steven H. Lin, Songbing Qin, Xiaohua Wang, Betty Y.S. Kim, Penghui Zhou, Wen Jiang, Qingyu Wu, Yuhui Huang

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Figure 1

ICB increases tumor vessel perfusion in treatment-sensitive, but not treatment-resistant, breast tumor models.

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ICB increases tumor vessel perfusion in treatment-sensitive, but not tre...
Mice bearing orthotopic breast tumors (MMTV-PyVT, EO771, 4T1, or MCaP0008) were treated with an anti–CTLA4 antibody or an isotype-matched control antibody (MPC11) every 3 days for a total of 4 doses; tumor size was measured every 3 days. Vessel perfusion of tumor tissues was assessed by confocal microscopy. (A) Anti–CTLA4 therapy inhibited tumor growth and increased vessel perfusion in EO771 breast tumors. Scale bars: 100 μM. (B) Anti–CTLA4 therapy reduced tumor tissue hypoxia in EO771 breast tumors. Scale bars: 1,000 or 100 μM. (C) Anti–CTLA4 therapy induced tumor regression and improved vessel perfusion in MMTV-PyVT breast tumors. Scale bars: 100 μM. MFI, mean fluorescence intensity; Ho33342 (blue), Hoechst 33342 perfused area; CD31 (red), endothelial cells; NG2 (green), pericytes; and Sytox Green (green), counterstained for tumor tissue. Significance was determined by unpaired 2-tailed Student’s t tests. Data are from 1 experiment representative of 3 independent experiments with similar results (n = 8–10 mice per group in A and B; n = 7–8 mice per group in C). All data are mean ± SEM. **P < 0.01, ***P < 0.001.