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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 ORCID:, 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: 17 May 2023 10:56

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