TY - JOUR
T1 - Low-dose anti-angiogenic therapy sensitizes breast cancer to PD-1 blockade
AU - Li, Qian
AU - Wang, Yifan
AU - Jia, Weijuan
AU - Deng, Heran
AU - Li, Guangdi
AU - Deng, Weiye
AU - Chen, Jiewen
AU - Kim, Betty Y.S.
AU - Jiang, Wen
AU - Liu, Qiang
AU - Liu, Jieqiong
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-2179
DO - 10.1158/1078-0432.CCR-19-2179
M3 - Article
C2 - 31848190
AN - SCOPUS:85082956707
SN - 1078-0432
VL - 26
SP - 1712
EP - 1724
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -