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Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade
Qian Li1,2, Yifan Wang3, Weijuan Jia1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
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 CD8+ T cells. OPN subsequently induces tumor cell production of TGF-β, 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-β 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.
Insights
Combining low-dose anti-angiogenic therapy with PD-1 blockade enhances anti-tumor immunity in breast cancer. This approach optimizes immune cell infiltration and activation, improving treatment response in patients with triple-negative breast cancer.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Cancer immunotherapy, particularly immune checkpoint inhibitors, shows promise but has suboptimal response rates in breast cancer.
- Combining immunotherapy with targeted agents like anti-angiogenic drugs is of increasing interest to enhance antitumor effects.
- The optimal combination strategies and mechanisms underlying synergistic responses between anti-angiogenic therapy and immune checkpoint blockade are not fully understood.
Purpose of the Study:
- To investigate the dose-dependent efficacy of combining anti-PD-1 therapy with VEGFR2-targeting agents in breast cancer models.
- To elucidate the immunological and molecular mechanisms driving synergistic responses between anti-angiogenic therapy and PD-1 blockade.
- To evaluate the clinical efficacy and tolerability of this combined therapy in patients with advanced triple-negative breast cancer (TNBC).
Main Methods:
- Syngeneic breast cancer mouse models were used to test combinations of anti-PD-1 and varying doses of VEGFR2-targeting agents.
- Tumor-infiltrated immune cell subsets were analyzed using flow cytometry.
- Cytokine arrays identified inflammatory changes, and clinical efficacy was assessed in TNBC patients.
Main Results:
- VEGFR2 blockade sensitized breast tumors to PD-1 blockade in a dose-dependent manner.
- Low-dose VEGFR2 blockade enhanced immune cell infiltration and activation, promoting osteopontin (OPN) secretion by CD8+ T cells.
- OPN induced TGF-β production by tumor cells, upregulating PD-1 on immune cells. Clinical evaluation in TNBC patients showed excellent tolerability and efficacy, with higher OPN and TGF-β correlating with better responses.
Conclusions:
- A dose-dependent synergism exists between anti-angiogenic therapy and immune checkpoint blockade in breast cancer.
- Low-dose VEGFR2 blockade represents an optimal strategy for enhancing immunotherapy efficacy by modulating the tumor microenvironment.
- These findings provide crucial insights for optimizing combination strategies in cancer immunotherapy.
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