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Increased vessel perfusion predicts the efficacy of immune checkpoint blockade
Xichen Zheng, … , Qingyu Wu, Yuhui Huang
Xichen Zheng, … , Qingyu Wu, Yuhui Huang
Published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2104-2115. https://doi.org/10.1172/JCI96582.
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Research Article Immunology Vascular biology Article has an altmetric score of 9

Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

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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 4

In vivo depletion of T cells reverses IVP and the inhibition of tumor growth induced by anti–CTLA4 therapy.

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In vivo depletion of T cells reverses IVP and the inhibition of tumor gr...
When EO771 breast tumors reached 3–4 mm in diameter, mice were randomly assigned to 4 groups and treated with anti–CD8 and anti–CD4 antibodies, or isotype 2A3 antibody (200 μg/mouse each) on days 0, 2, and 8. On day 1, mice were further treated with an anti–CTLA4 antibody or MPC11 (5 mg/kg) every 3 days for 4 doses. (A) In vivo depletion of CD8+ and CD4+ T cells completely eliminated the antitumor effect of anti–CTLA4 therapy. (B) Anti–CD8 and anti–CD4 antibody coadministration eradicated tumor-infiltrating T cells. (C and D) In vivo depletion of CD8+ and CD4+ T cells reversed IVP induced by anti–CTLA4 therapy. Scale bars: 100 μM. (E) In vivo depletion of CD8+ and CD4+ T cells abolished the effects of anti–CTLA4 therapy on the transcription of genes related to antitumor immunity. Significance was determined by 1-way ANOVA with Bonferroni’s adjusted post hoc t tests for multiple comparisons. Data are from 1 experiment representative of 2 independent experiments (n = 8–10 mice per group). *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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