title: Intrinsically de-sialylated CD103(+) CD8 T cells mediate beneficial anti-glioma immune responses.
abstract: BACKGROUND
  Cancer vaccines reproducibly cure laboratory animals and reveal encouraging trends in brain tumor (glioma) patients. Identifying parameters governing beneficial vaccine-induced responses may lead to the improvement of glioma immunotherapies. CD103(+) CD8 T cells dominate post-vaccine responses in human glioma patients for unknown reasons, but may be related to recent thymic emigrant (RTE) status. Importantly, CD8 RTE metrics correlated with beneficial immune responses in vaccinated glioma patients.
  
  
  METHODS
  We show by flow cytometry that murine and human CD103(+) CD8 T cells respond better than their CD103(-) counterparts to tumor peptide-MHC I (pMHC I) stimulation in vitro and to tumor antigens on gliomas in vivo.
  
  
  RESULTS
  Glioma responsive T cells from mice and humans both exhibited intrinsic de-sialylation-affecting CD8 beta. Modulation of CD8 T cell sialic acid with neuraminidase and ST3Gal-II revealed de-sialylation was necessary and sufficient for promiscuous binding to and stimulation by tumor pMHC I. Moreover, de-sialylated status was required for adoptive CD8 T cells and lymphocytes to decrease GL26 glioma invasiveness and increase host survival in vivo. Finally, increased tumor ST3Gal-II expression correlated with clinical vaccine failure in a meta-analysis of high-grade glioma patients.
  
  
  CONCLUSIONS
  Taken together, these findings suggest that de-sialylation of CD8 is required for hyper-responsiveness and beneficial anti-glioma activity by CD8 T cells. Because CD8 de-sialylation can be induced with exogenous enzymes (and appears particularly scarce on human T cells), it represents a promising target for clinical glioma vaccine improvement.
authors.affiliation: Department of Neurosurgery, Cedars Sinai Medical Center, Advanced Health Sciences Pavilion, Maxine Dunitz Neurosurgical Institute, 127 S. San Vicente Blvd, Suite A8113, Los Angeles, CA, 90048, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jouanneau
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Lucia
authors.initials: L
authors.lastname: Veiga
authors.forename: Ryan
authors.initials: R
authors.lastname: Cordner
authors.forename: Shyam
authors.initials: S
authors.lastname: Goverdhana
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhai
authors.forename: Xiao-xue
authors.initials: XX
authors.lastname: Zhang
authors.forename: Akanksha
authors.initials: A
authors.lastname: Panwar
authors.forename: Armen
authors.initials: A
authors.lastname: Mardiros
authors.forename: HongQiang
authors.initials: H
authors.lastname: Wang
authors.forename: Ashley
authors.initials: A
authors.lastname: Gragg
authors.forename: Mandana
authors.initials: M
authors.lastname: Zandian
authors.forename: Dwain K
authors.initials: DK
authors.lastname: Irvin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D005910:Glioma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D039001:Integrin alpha Chains / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000378:metabolism / Q000494:pharmacology; D012799:Sialyltransferases / Q000378:metabolism / Q000494:pharmacology; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D015703:Antigens, CD; D019496:Cancer Vaccines; D039001:Integrin alpha Chains; C091367:alpha E integrins; D012799:Sialyltransferases; D009439:Neuraminidase; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase