title: Peripheral blood-derived, γ9δ2 t cell-enriched cell lines from glioblastoma multiforme patients exert anti-tumoral effects in vitro.
abstract: The goal of this work was to assess the potential of T cells expressing Vγ9Vδ2+ T cell receptors (TCR, γ9δ2T cells) present in peripheral blood (PB) m ononuclear cells (MC, PBMC) of glioblastoma multiforme (GBM) patients to act as anti-tumoral agents. We found that γ9δ2T cell levels were decreased in patients' PB relative to a cohort of healthy donors (HD) (respectively 0.52±0.55%, n=16, vs 1.12±0.6%, n=14, p=0.008) but did not significantly correlate with postoperative survival (R=0.6, p=0.063). Importantly, however, the γ9δ2T cells could be expanded in vitro to consist 51±23% of the cultured lymphocytes (98% CD3+). This was achieved after 14 days of culture in medium containing the amino-bisphosphonate (ABP) Zoledronate (Zol) and interleukin (IL)-2, resulting in γ9δ2T cell-enriched lines (gdTCEL) similar to those of HD derived gdTCEL (54±19%). Moreover, gdTCEL from patients and HD mediated cytotoxicity to GBM-derived cell lines (GBMDCL), which was abrogated by immune-magnetic removal of the γ9δ2T cells. Furthermore, low level interferon (IFN) γ secretion was induced by gdTCEL briefly co-cultured with GBMDCL or autologous - tumor-derived cells, which was greatly amplified in the presence of Zol. Importantly, IFNγ secretion was inhibited by mevastatin but enhanced by cross-linking of butyrophilin 3A1 (CD277) on a CD277+ GBMDCL (U251MG) or by pretreatment of GBMDCL with temozolomide (TMZ). Taken together, these data suggest that γ9δ2T cells in PB of GBM patients can give rise to gdTCEL that mediate anti-tumoral activities.
authors.affiliation: Laboratory for Immunoregulation, Sheba Medical Center, Tel Hashomer, Israel; Institute of Hematology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Marcu-Malina
authors.affiliation: Department of Medicine F, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Garelick
authors.affiliation: Department of Neurosurgery, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Peshes-Yeloz
authors.affiliation: Department of Neurosurgery, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Wohl
authors.affiliation: Institute of Oncology and Radiotherapy, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Zach
authors.affiliation: Institute of Hematology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Nagar
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Israel; Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: M J
authors.initials: MJ
authors.lastname: Besser
authors.affiliation: Department of Neurosurgery, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Z R
authors.initials: ZR
authors.lastname: Cohen
authors.affiliation: Laboratory for Immunoregulation, Sheba Medical Center, Tel Hashomer, Israel; Department of Medicine F, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Bank
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D001932:Brain Neoplasms / Q000097:blood* / Q000276:immunology / Q000473:pathology*; D000071797:Butyrophilins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005909:Glioblastoma / Q000097:blood* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D000077204:Temozolomide; D014019:Tissue Donors
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C558381:BTN3A1 protein, human; D000071797:Butyrophilins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C012258:mevastatin; D003606:Dacarbazine; D007371:Interferon-gamma; D008148:Lovastatin; D008798:Mevalonic Acid; D000077204:Temozolomide