Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles
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...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-12-01
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| Series: | OncoImmunology |
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| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1362530 |
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| author | Vanesa G. Martinez Sadhbh O'Neill Josephine Salimu Susan Breslin Aled Clayton John Crown Lorraine O'Driscoll |
| author_facet | Vanesa G. Martinez Sadhbh O'Neill Josephine Salimu Susan Breslin Aled Clayton John Crown Lorraine O'Driscoll |
| author_sort | Vanesa G. Martinez |
| collection | DOAJ |
| description | 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 with 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-tumor 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. |
| first_indexed | 2024-12-13T12:01:37Z |
| format | Article |
| id | doaj.art-596b2cf4b1194c95b866c6402663e962 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-13T12:01:37Z |
| publishDate | 2017-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-596b2cf4b1194c95b866c6402663e9622022-12-21T23:47:05ZengTaylor & Francis GroupOncoImmunology2162-402X2017-12-0161210.1080/2162402X.2017.13625301362530Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesiclesVanesa G. Martinez0Sadhbh O'Neill1Josephine Salimu2Susan Breslin3Aled Clayton4John Crown5Lorraine O'Driscoll6School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College DublinSchool of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College DublinInstitute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer CentreSchool of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College DublinInstitute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer CentreSt Vincent's University HospitalSchool of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College DublinNeuromedin 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 with 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-tumor 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.http://dx.doi.org/10.1080/2162402X.2017.1362530biomarkerextracellular vesicles: exosomesimmune evasionneo-adjuvant clinical trialneuromedin u |
| spellingShingle | Vanesa G. Martinez Sadhbh O'Neill Josephine Salimu Susan Breslin Aled Clayton John Crown Lorraine O'Driscoll Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles OncoImmunology biomarker extracellular vesicles: exosomes immune evasion neo-adjuvant clinical trial neuromedin u |
| title | Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles |
| title_full | Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles |
| title_fullStr | Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles |
| title_full_unstemmed | Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles |
| title_short | Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles |
| title_sort | resistance to her2 targeted anti cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles |
| topic | biomarker extracellular vesicles: exosomes immune evasion neo-adjuvant clinical trial neuromedin u |
| url | http://dx.doi.org/10.1080/2162402X.2017.1362530 |
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