title: CD4(+) T-Helper Type 1 Cytokines and Trastuzumab Facilitate CD8(+) T-cell Targeting of HER2/neu-Expressing Cancers.
abstract: Vaccination strategies incorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2369-377) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2369-377-specific CD8(+) T cells to recognize HLA-A2(pos)HER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2369-377 is directly recognized by high functional-avidity HER2369-377-specific CD8(+) T cells-either genetically modified to express a novel HER2369-377 TCR or sensitized using HER2369-377-pulsed type 1-polarized dendritic cells (DC1)-on class I-abundant HER2(low), but not class I-deficient HER2(high), cancer cells. Importantly, a critical cooperation between CD4(+) T-helper type-1 (Th1) cytokines IFNγ/TNFα and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2(high) cancers, thereby facilitating recognition and lysis of these cells by HER2369-377-specific CD8(+) T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNγ/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2369-377-CD8(+) T-cell-mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNγ/TNFα and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2369-377-CD8(+) cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4(+) Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neu CD8(+) T-cell-directed immunotherapy.
authors: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Jashodeep
authors: J
authors: Datta
authors: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Shuwen
authors: S
authors: Xu
authors: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Cinthia
authors: C
authors: Rosemblit
authors: Department of Pathology and Laboratory Medicine; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Jenessa B
authors: JB
authors: Smith
authors: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Jessica A
authors: JA
authors: Cintolo
authors: Department of Pathology and Laboratory Medicine; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Daniel J
authors: DJ
authors: Powell
authors: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. brian.czerniecki@uphs.upenn.edu.
authors: Brian J
authors: BJ
authors: Czerniecki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009369:Neoplasms / Q000276:immunology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000068878:Trastuzumab / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014409:Tumor Necrosis Factor-alpha; C561872:HER2 peptide (369-377)