title: Progressive loss of anti-HER2 CD4+T-helper type 1 response in breast tumorigenesis and the potential for immune restoration.
abstract: Genomic profiling has identified several molecular oncodrivers in breast tumorigenesis. A thorough understanding of endogenous immune responses to these oncodrivers may provide insights into immune interventions for breast cancer (BC). We investigated systemic anti-HER2/neuCD4+T-helper type-1 (Th1) responses in HER2-driven breast tumorigenesis. A highly significant stepwise Th1 response loss extending from healthy donors (HD), through HER2pos-DCIS, and ultimately to early stage HER2pos-invasive BC patients was detected by IFNγ ELISPOT. The anti-HER2 Th1 deficit was not attributable to host-level T-cell anergy, loss of immune competence, or increase in immunosuppressive phenotypes (Treg/MDSCs), but rather associated with a functional shift in IFNγ:IL-10-producing phenotypes. HER2high, but not HER2low, BC cells expressing IFNγ/TNF-α receptors were susceptible to Th1 cytokine-mediated apoptosisin vitro, which could be significantly rescued by neutralizing IFNγ and TNF-α, suggesting that abrogation of HER2-specific Th1 may reflect a mechanism of immune evasion in HER2-driven tumorigenesis. While largely unaffected by cytotoxic or HER2-targeted (trastuzumab) therapies, depressed Th1 responses in HER2pos-BC patients were significantly restored following HER2-pulsed dendritic cell (DC) vaccinations, suggesting that this Th1 defect is not "fixed" and can be corrected by immunologic interventions. Importantly, preserved anti-HER2 Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy, while depressed responses were observed in patients incurring locoregional/systemic recurrence following trastuzumab/chemotherapy. Monitoring anti-HER2 Th1 reactivity following HER2-directed therapies may identify vulnerable subgroups at risk of clinicopathologic failure. In such patients, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 CD4+Th1 immunity may decrease the risk of recurrence and thus warrant further investigation.
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Jashodeep
authors.initials: J
authors.lastname: Datta
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Rosemblit
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Berk
authors.affiliation: Department of Biological Sciences; Kent State University ; Kent, OH USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Showalter
authors.affiliation: Department of Biological Sciences; Kent State University ; Kent, OH USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Namjoshi
authors.affiliation: Department of Epidemiology and Biostatistics; University of Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Kathreen P
authors.initials: KP
authors.lastname: Lee
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Brod
authors.affiliation: Department of Surgery; Stanford University Hospital and Clinics ; Palo Alto, CA USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Yang
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Kelz
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fitzpatrick
authors.affiliation: Life Sciences & Technology; PerkinElmer Inc. ; Hopkinton, MA USA.
authors.forename: Clifford
authors.initials: C
authors.lastname: Hoyt
authors.affiliation: Department of Pathology; University of Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Department of Pathology; University of Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences; Kent State University ; Kent, OH USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Koski
authors.affiliation: Department of Surgery; University Pennsylvania Perelman School of Medicine ; Philadelphia, PA USA ; Rena Rowen Breast Center; Hospital of the University of Pennsylvania ; Philadelphia, PA USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
keywords: CD4+ T-helper immunity; HER2/neu; breast cancer; dendritic cell; immune monitoring; immune restoration; vaccination