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Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis
John Stagg1, Upulie Divisekera, Nicole McLaughlin
1Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. john.stagg@petermac.org
Abstract:
Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73, an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1.2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5'-N-ethylcarboxamide to tumor-bearing mice significantly enhanced spontaneous 4T1.2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 4T1.2 tumor-cell chemotaxis in vitro and metastasis in vivo. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer.
Insights
Targeting CD73, an enzyme on breast cancer cells, with monoclonal antibodies (mAbs) inhibits tumor growth and metastasis. This therapy activates anti-tumor immunity, offering a new strategy for breast cancer treatment.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Extracellular adenosine suppresses the immune system and promotes tumor growth.
- CD73, an ecto-enzyme, generates adenosine by dephosphorylating adenosine monophosphates.
- CD73 is overexpressed on breast cancer cells, contributing to immune escape and metastasis.
Purpose of the Study:
- To investigate the therapeutic potential of anti-CD73 monoclonal antibody (mAb) therapy against breast cancer.
- To elucidate the mechanism of action of CD73 in tumor growth, immune suppression, and metastasis.
- To establish proof-of-concept for targeting CD73 to enhance anti-tumor immunity and inhibit metastasis.
Main Methods:
- Administered anti-CD73 mAb therapy to mice with 4T1.2 and E0771 breast tumors.
- Assessed tumor growth, lung metastasis development, and adaptive anti-tumor immune responses.
- Utilized CD73 knockdown in tumor cells and adenosine receptor antagonists to study CD73's function.
Main Results:
- Anti-CD73 mAb therapy significantly delayed primary tumor growth and inhibited lung metastasis in mice.
- Therapeutic efficacy was dependent on the induction of adaptive anti-tumor immune responses.
- CD73 knockdown confirmed its tumor-promoting effects; CD73 also enhanced tumor cell chemotaxis and metastasis via A2B adenosine receptors.
Conclusions:
- Tumor-derived CD73 is a key mechanism for immune escape and metastasis in breast cancer.
- Targeting CD73 with mAbs can trigger adaptive anti-tumor immunity.
- Anti-CD73 mAb therapy shows promise in inhibiting breast cancer metastasis and growth.
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