Breast Cancer Stem Cell–Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands
Creators: name: Raute, Katrin
name: Strietz, Juliane
name: Parigiani, Maria Alejandra
name: Andrieux, Geoffroy
name: Thomas, Oliver S.
name: Kistner, Klaus M.
name: Zintchenko, Marina
name: Aichele, Peter
name: Hofmann, Maike
name: Zhou, Houjiang
name: Weber, Wilfried
name: Boerries, Melanie
name: Swamy, Mahima
name: Maurer, Jochen
name: Minguet, Susana
Publisher: name: Philadelphia, Pa. : AACR
Year: 2023
Subjects: subject: Animals
subject: Humans
subject: Mice
subject: Monitoring, Immunologic
subject: Neoplasm Recurrence, Local
subject: Neoplastic Stem Cells
subject: Receptors, Antigen, T-Cell, gamma-delta
subject: Triple Negative Breast Neoplasms
subject: alpha interferon
subject: cell adhesion molecule
subject: compactin
subject: matrix metalloproteinase 14
subject: nivolumab
subject: proteome
subject: zoledronic acid
subject: lymphocyte antigen receptor
subject: animal cell
subject: animal experiment
subject: animal model
subject: antigen recognition
subject: antigenic escape
subject: Article
subject: breast cancer
subject: cancer immunotherapy
subject: cancer stem cell
subject: cell differentiation
subject: cell expansion
subject: chromium release assay
subject: controlled study
subject: cytotoxicity
subject: enzyme activity
subject: ex vivo study
subject: fibroblast
subject: flow cytometry
subject: gamma delta T lymphocyte
subject: human
subject: human cell
subject: immune response
subject: immunosurveillance
subject: in vivo study
subject: mass spectrometry
subject: mouse
subject: nonhuman
subject: overall survival
subject: peripheral blood mononuclear cell
subject: reversed phase liquid chromatography
subject: RNA sequencing
subject: Sanger sequencing
subject: scanning electron microscopy
subject: transwell assay
subject: triple negative breast cancer
subject: upregulation
subject: xenotransplantation
subject: animal
subject: immunological monitoring
subject: metabolism
subject: pathology
subject: tumor recurrence
subject: 610

description: There are no targeted therapies for patients with triple-negative breast cancer (TNBC). TNBC is enriched in breast cancer stem cells (BCSC), which play a key role in metastasis, chemoresistance, relapse, and mortality. γδ T cells hold great potential in immunotherapy against cancer and might provide an approach to therapeutically target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor-sensing mechanisms, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. Herein, we show that patient-derived triple-negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γ δ T-cell immunotherapy. We unraveled concerted differentiation and immune escape mechanisms: xenografted BCSCs lost stemness, expression of γ δ T-cell ligands, adhesion molecules, and pAgs, thereby evading immune recognition by γ δ T cells. Indeed, neither promigratory engineered γ δ T cells, nor anti–PD-1 checkpoint blockade, significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γ δ T cells and could be pharmacologically reverted by zoledronate or IFNα treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.