Increased vessel perfusion predicts the efficacy of immune checkpoint blockade
Open accessAbstract
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.
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Better tumor blood vessels support adaptive antitumor immunity by helping tumor-infiltrating lymphocytes traffic and relocate, which improves results of immunotherapies such as immune checkpoint blockade.
“An improved vascular network favors adaptive antitumor immunity by promoting trafficking and re-localization of tumor-infiltrating lymphocytes (TILs), leading to improved outcomes of various immunotherapies, including immune checkpoint blockade (ICB) (15-20).”
Vascular normalization can increase immune cell infiltration into tumors.
“We previously demonstrated that vascular normalization could increase immune cells’ infiltration into tumors, and multiple studies have confirmed these findings in several tumor models (15,17-19).”
Poor perfusion, tumor hypoxia, and T-cell exclusion are regarded as major resistance mechanisms.
“Lack of perfusion, tumoral hypoxia, and T-cell exclusion are considered significant resistance mechanisms (15,17-19).”
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Self-citation
- Authors
- Zheng, X., Fang, Z., Liu, X., Deng, S., Zhou, P., Wang, X., Zhang, C., Yin, R., Hu, H., Chen, X., Han, Y., Zhao, Y., Lin, S. H., Qin, S., Wang, X., Kim, B. Y. S., Zhou, P., Jiang, W., Wu, Q., & Huang, Y.
- Affiliations
- Sun Yat-sen University Cancer Center (CN)
- First Affiliated Hospital of Soochow University (CN)
- Soochow University (CN)
- Chinese Academy of Sciences (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Huang, Yuhui
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-04-16
- Volume
- 128
- Issue
- 5
- Pages
- 2104-2115
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5957454
- OpenAlex
- W2800799386
- Cited by
- 239
- References
- 48
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 40 · 2023: 47 · 2022: 33 · 2021: 31 · 2020: 28 · 2019: 9 · 2018: 5
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the National Natural Science Foundation of China (81372245, 81673004)
- the National Program on Key Research Project of China (2016YFC1302400)
- the National Institute of Neurological Disorders and Stroke (R01 NS104315)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- immune checkpoint blockade, predictive biomarkers, CTLA-4, PD-1, CD8+ T cells, interferon-gamma, T cell-mediated antitumor immunity, Doppler ultrasound, breast cancer, colon cancer, treatment resistance, tumor microvasculature
- MeSH terms
- Animals, Colonic Neoplasms, Interferon-gamma, Lymphocyte Depletion, Mammary Neoplasms, Experimental, Perfusion, CD8-Positive T-Lymphocytes, Mice
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