title: Exosomal pMHC-I complex targets T cell-based vaccine to directly stimulate CTL responses leading to antitumor immunity in transgenic FVBneuN and HLA-A2/HER2 mice and eradicating trastuzumab-resistant tumor in athymic nude mice.
abstract: One of the major obstacles in human epidermal growth factor receptor 2 (HER2)-specific trastuzumab antibody immunotherapy of HER2-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Using mouse models, we previously demonstrated that ovalbumin (OVA)-specific dendritic cell (DC)-released exosome (EXOOVA)-targeted CD4(+) T cell-based (OVA-TEXO) vaccine stimulates efficient cytotoxic T lymphocyte (CTL) responses via exosomal peptide/major histocompatibility complex (pMHC)-I, exosomal CD80 and endogenous IL-2 signaling; and long-term CTL memory by means of via endogenous CD40L signaling. In this study, using two-photon microscopy, we provide the first visual evidence on targeting OVA-TEXO to cognate CD8(+) T cells in vivo via exosomal pMHC-I complex. We prepared HER2/neu-specific Neu-TEXO and HER2-TEXO vaccines using adenoviral vector (AdVneu and AdVHER2)-transfected DC (DCneu and DCHER2)-released EXOs (EXOneu and EXOHER2), and assessed their stimulatory effects on HER2/neu-specific CTL responses and antitumor immunity. We demonstrate that Neu-TEXO vaccine is capable of stimulating efficient neu-specific CTL responses, leading to protective immunity against neu-expressing Tg1-1 breast cancer in all 6/6 transgenic (Tg) FVBneuN mice with neu-specific self-immune tolerance. We also demonstrate that HER2-TEXO vaccine is capable of inducing HER2-specific CTL responses and protective immunity against transgene HLA-A2(+)HER2(+) BL6-10A2/HER2 B16 melanoma in 2/8 double Tg HLA-A2/HER2 mice with HER2-specific self-immune tolerance. The remaining 6/8 mice had significantly prolonged survival. Furthermore, we demonstrate that HER2-TEXO vaccine stimulates responses of CD8(+) T cells capable of not only inducing killing activity to HLA-A2(+)HER2(+) BL6-10A2/HER2 melanoma and trastuzumab-resistant BT474A2 breast cancer cells in vitro but also eradicating 6-day palpable HER2(+) BT474A2 breast cancer (3-4 mm in diameter) in athymic nude mice. Therefore, the novel T cell-based HER2-TEXO vaccine may provide a new therapeutic alternative for women with HER2(+) breast cancer, especially for trastuzumab-resistant HER2(+) breast cancer patients.
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK, Canada.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.forename: Khawaja Ashfaque
authors.initials: KA
authors.lastname: Ahmed
authors.forename: Shahid
authors.initials: S
authors.lastname: Ahmed
authors.forename: Amer
authors.initials: A
authors.lastname: Sami
authors.forename: Rajni
authors.initials: R
authors.lastname: Chibbar
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Xu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kane
authors.forename: Siguo
authors.initials: S
authors.lastname: Hao
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulligan
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology*; D055354:Exosomes / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human