title: Human Vγ2Vδ2 T cells limit breast cancer growth by modulating cell survival-, apoptosis-related molecules and microenvironment in tumors.
abstract: Innate immune system has been known to play an important role in inhibiting the malignant transformation, tumor progression and invasion. However, the mechanistic basis remains ambiguous. Despite polyclonality of human γδ T cells, Vγ2Vδ2 T cell subset was shown to recognize and limit the growth of various tumors at various degrees. The differential recognition of the tumor cells by Vγ2Vδ2 T cells are yet to be defined. Our study reveals that γδ T cells limit in vitro growth of most breast tumor cells, such as SkBr7 (HER2+), MCF7 (ER+) and MDA-MB-231 (ER-) by inhibiting their survival and inducing apoptosis, except BrCa-MZ01 (PR+) cells. To investigate detail mechanisms of antineoplastic effects, we found that cell death was associated with the surface expression levels of MICA/B and ICAM1. Molecular signaling analysis demonstrated that inhibition of cell growth by γδ T cells was associated with the lower expression levels of cell survival-related molecules such as AKT, ERK and concomitant upregulation of apoptosis-related molecules, such as PARP, cleaved caspase 3 and tumor suppressor genes PTEN and P53. However, opposite molecular signaling was observed in the resistant cell line after coculture with γδ T cells. In vivo, antineoplastic effects of γδ T cells were also documented, where tumor growth was inhibited due to the downregulation of survival signals, strong induction of apoptotic molecules, disruption of microvasculature and increased infiltration of tumor associated macrophages. These findings reveal that a complex molecular signaling is involved in γδ T cell-mediated antineoplastic effects.
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Wexner Medical Center at The Ohio State University, Columbus, OH, USA.
authors.forename: Reeva
authors.initials: R
authors.lastname: Aggarwal
authors.forename: Jingwei
authors.initials: J
authors.lastname: Lu
authors.forename: Suman
authors.initials: S
authors.lastname: Kanji
authors.forename: Manjusri
authors.initials: M
authors.lastname: Das
authors.forename: Matthew
authors.initials: M
authors.lastname: Joseph
authors.forename: Maryam B
authors.initials: MB
authors.lastname: Lustberg
authors.forename: Alo
authors.initials: A
authors.lastname: Ray
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Pompili
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Hiranmoy
authors.initials: H
authors.lastname: Das
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: NOD/SCID mice; Vγ2Vδ2 T cell; angiogenesis; apoptosis; breast cancer; cell survival; xenotransplant