Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

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, Y S Betty Kim, Penghui Zhou, Wen Jiang, Qingyu Wu, Yuhui Huang

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2104-2115
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Perfusion
Neoplasms
T-Lymphocytes
Breast Neoplasms
Doppler Ultrasonography
Cytotoxic T-Lymphocytes
Therapeutics
Knockout Mice
Immunity
Colon
Cell Death
Biomarkers
Sensitivity and Specificity
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zheng, X., Fang, Z., Liu, X., Deng, S., Zhou, P., Wang, X., ... Huang, Y. (2018). Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. Journal of Clinical Investigation, 128(5), 2104-2115. https://doi.org/10.1172/JCI96582

Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. / Zheng, Xichen; Fang, Zhaoxu; Liu, Xiaomei; Deng, Shengming; Zhou, Pei; Wang, Xuexiang; Zhang, Chenglin; Yin, Rongping; Hu, Haitian; Chen, Xiaolan; Han, Yijie; Zhao, Yun; Lin, Steven H.; Qin, Songbing; Wang, Xiaohua; Kim, Y S Betty; Zhou, Penghui; Jiang, Wen; Wu, Qingyu; Huang, Yuhui.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 2104-2115.

Research output: Contribution to journalArticle

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, SH, Qin, S, Wang, X, Kim, YSB, Zhou, P, Jiang, W, Wu, Q & Huang, Y 2018, 'Increased vessel perfusion predicts the efficacy of immune checkpoint blockade', Journal of Clinical Investigation, vol. 128, no. 5, pp. 2104-2115. https://doi.org/10.1172/JCI96582
Zheng, Xichen ; Fang, Zhaoxu ; Liu, Xiaomei ; Deng, Shengming ; Zhou, Pei ; Wang, Xuexiang ; Zhang, Chenglin ; Yin, Rongping ; Hu, Haitian ; Chen, Xiaolan ; Han, Yijie ; Zhao, Yun ; Lin, Steven H. ; Qin, Songbing ; Wang, Xiaohua ; Kim, Y S Betty ; Zhou, Penghui ; Jiang, Wen ; Wu, Qingyu ; Huang, Yuhui. / Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 2104-2115.
@article{ef3dec19145643cf9e3fcc95a31b8afc,
title = "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.",
author = "Xichen Zheng and Zhaoxu Fang and Xiaomei Liu and Shengming Deng and Pei Zhou and Xuexiang Wang and Chenglin Zhang and Rongping Yin and Haitian Hu and Xiaolan Chen and Yijie Han and Yun Zhao and Lin, {Steven H.} and Songbing Qin and Xiaohua Wang and Kim, {Y S Betty} and Penghui Zhou and Wen Jiang and Qingyu Wu and Yuhui Huang",
year = "2018",
month = "5",
day = "1",
doi = "10.1172/JCI96582",
language = "English (US)",
volume = "128",
pages = "2104--2115",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

AU - Zheng, Xichen

AU - Fang, Zhaoxu

AU - Liu, Xiaomei

AU - Deng, Shengming

AU - Zhou, Pei

AU - Wang, Xuexiang

AU - Zhang, Chenglin

AU - Yin, Rongping

AU - Hu, Haitian

AU - Chen, Xiaolan

AU - Han, Yijie

AU - Zhao, Yun

AU - Lin, Steven H.

AU - Qin, Songbing

AU - Wang, Xiaohua

AU - Kim, Y S Betty

AU - Zhou, Penghui

AU - Jiang, Wen

AU - Wu, Qingyu

AU - Huang, Yuhui

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85046488349&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046488349&partnerID=8YFLogxK

U2 - 10.1172/JCI96582

DO - 10.1172/JCI96582

M3 - Article

C2 - 29664018

AN - SCOPUS:85046488349

VL - 128

SP - 2104

EP - 2115

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -