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Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles

Martinez, Vanesa G., O'Neill, Sadhbh, Salimu, Josephine, Breslin, Susan, Clayton, Aled, Crown, John and O'Driscoll, Lorraine 2017. Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles. OncoImmunology 6 (12) , e1362530. 10.1080/2162402X.2017.1362530

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Neuromedin U (NmU) -a neuropeptide belonging to the neuromedin family– plays a substantial role in HER2-positive breast cancer, correlating with increased aggressiveness, resistance to HER2-targeted therapies and overall significantly poorer outcome for patients. However, the mechanism through which it exerts these effects remains unclear. To elucidate this, initially we used HER2-positive breast cancer cells stably over-expressing NmU. These cells and their released extracellular vesicles (EVs) had increased amounts of the immunosuppressive cytokine TGFβ1 and the lymphocyte activation inhibitor PD-L1. Furthermore, these cells also showed enhanced resistance to antibody-dependent cell cytotoxicity (ADCC) mediated by trastuzumab, indicating a role of NmU in enhancing immune evasion. All these features were also found in HER2-targeted drug-resistant cells which we previously found to express higher levels of NmU than their drug-sensitive counterparts. Interestingly, EVs from drug-resistant cells were able to increase levels of TGFβ1 in drug-sensitive cells. In our neo-adjuvant clinical trial, TGFβ1 levels were significantly higher in EVs isolated from the serum of patients with HER2-overexpressing breast cancers who went on to not respond to HER2-targeted drug treatment, compared to those who experienced complete or partial response. Taken together, our results report a new mechanism-of-action for NmU in HER2-overexpressing breast cancer that enhances resistance to the anti-tumour immune response. Furthermore, EV levels of TGFβ1 correlating with patients' response versus resistance to HER2-targeted drugs suggests a potential use of EV-TGFβ1 as a minimally-invasive companion diagnostic for such treatment in breast cancer.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Taylor & Francis
ISSN: 2162-4011
Date of First Compliant Deposit: 18 October 2017
Date of Acceptance: 28 July 2017
Last Modified: 20 May 2020 10:45

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