Low-dose anti-angiogenic therapy sensitizes breast cancer to PD-1 blockade

Qian Li, Yifan Wang, Weijuan Jia, Heran Deng, Guangdi Li, Weiye Deng, Jiewen Chen, Betty Y.S. Kim, Wen Jiang, Qiang Liu, Jieqiong Liu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: Despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal, especially in breast cancer. There is an increased interest in combining immune checkpoint inhibitor with targeted agents to enhance antitumor effect. Anti-angiogenic drugs have been shown to synergize with immune checkpoint blockades, but the optimal setting for combining these two modalities and the underlying mechanisms of synergistic responses are not fully understood. Experimental Design: We tested the combination of anti-PD-1 and different doses of VEGFR2-targeting agents in syngeneic breast cancer mouse models. Tumor-infiltrated immune cell subsets were profiled by flow cytometry. A cytokine array was carried out to identify inflammatory changes in different treatment conditions. The efficacy of combined anti-angiogenic and anti-PD-1 therapy was further evaluated in patients with advanced triple-negative breast cancer (TNBC). Results: Blockade of VEGFR2 sensitizes breast tumors to PD-1 blockade in a dose-dependent manner. Although both conventional and low-dose anti-VEGFR2 antibody treatments normalize tumor vessels, low-dose VEGFR2 blockade results in more robust immune cell infiltration and activation and promotes the secretion of osteopontin (OPN) by CD8þ T cells. OPN subsequently induces tumor cell production of TGF-b, which in turn upregulates PD-1 expression on immune cells. In patients with advanced TNBC, combined treatment with low-dose anti-VEGFR2 inhibitor and anti-PD-1 demonstrated excellent tolerability and efficacy. Higher OPN and TGF-b expressions correlated with improved treatment responses. Conclusions: Together, these results demonstrate a dose-dependent synergism between anti-angiogenic therapy and immune checkpoint blockade, thus providing important insights into the optimal strategies for combining immunotherapy with molecular-targeted agents.

Original languageEnglish (US)
Pages (from-to)1712-1724
Number of pages13
JournalClinical Cancer Research
Volume26
Issue number7
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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