A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice
| Autor: | Sae Gwang Park, Won Sik Lee, Joo Yeon Song, Jae Hyeog Choi, Kug Hwan Roh, Sung Su Yea, Su Kil Seo, Seung Jae Park, Hana Jung, Ji Young Lee, Il-Whan Choi, Ki Hyang Kim, Il Hwan Kim, Yang Xin Fu, Anbok Lee |
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| Rok vydání: | 2018 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine T cell Immunology anti-tumor immunity lcsh:RC254-282 03 medical and health sciences breast cancer 0302 clinical medicine Immune system Breast cancer Antigen Trastuzumab medicine Immunology and Allergy Epidermal growth factor receptor pi3k p110α-selective inhibitor Original Research biology Chemistry anti-her2/neu antibody lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Immunohistochemistry Antibody lcsh:RC581-607 medicine.drug |
| Zdroj: | OncoImmunology, Vol 7, Iss 5 (2018) |
| ISSN: | 2162-402X |
| DOI: | 10.1080/2162402x.2017.1421890 |
| Popis: | Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-human epidermal growth factor receptor [HER]2/neu antibody) are effective against HER2+ breast cancer. Isoform-selective PI3K inhibitors elicit anti-tumor immune responses that are distinct from those induced by inhibitors of class I PI3K isoforms (pan-PI3K inhibitors). The present study investigated the therapeutic effect and potential for stimulating anti-tumor immunity of combined therapy with an anti-HER2/neu antibody and pan-PI3K inhibitor (GDC-0941) or a PI3K p110α isoform-selective inhibitor (A66) in mouse models of breast cancer. The anti-neu antibody inhibited tumor growth and enhanced anti-tumor immunity in HER2/neu+ breast cancer TUBO models, whereas GDC-0941 or A66 alone did not. Anti-neu antibody and PI3K inhibitor synergistically promoted anti-tumor immunity by increasing functional T cell production. In the presence of the anti-neu antibody, A66 was more effective than GDC-0941 at increasing the fraction of CD4+, CD8+, and IFN-γ+CD8+ T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-γ levels by enzyme-linked immunospot assay showed that the numbers of tumor-specific T cells against neu and non-neu tumor antigens were increased by combined PI3K inhibitor plus anti-neu antibody treatment, with A66 exhibiting more potent effects than GDC-0941. In a TUBO (neu+) and TUBO-P2J (neu−) mixed tumor model representing immunohistochemistry 2+ tumors, A66 suppressed tumor growth and prolonged survival to a greater extent than GDC-0941 when combined with anti-neu antibody. These results demonstrate that a PI3K p110α-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer. |
| Databáze: | OpenAIRE |
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