Intrinsically de-sialylated CD103(+) CD8 T cells mediate beneficial anti-glioma immune responses

Cancer Immunol Immunother. 2014 Sep;63(9):911-24. doi: 10.1007/s00262-014-1559-2. Epub 2014 Jun 4.

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.

Trial registration: ClinicalTrials.gov NCT00576537 NCT00576641.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • Brain Neoplasms / immunology
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / immunology
  • Cancer Vaccines / pharmacology*
  • Dendritic Cells / immunology*
  • Female
  • Glioblastoma / immunology
  • Glioblastoma / metabolism
  • Glioblastoma / therapy
  • Glioma / immunology
  • Glioma / metabolism
  • Glioma / therapy*
  • Humans
  • Immunotherapy, Adoptive / methods
  • Integrin alpha Chains / immunology*
  • Integrin alpha Chains / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neuraminidase / metabolism
  • Neuraminidase / pharmacology
  • Sialyltransferases / metabolism
  • Sialyltransferases / pharmacology

Substances

  • Antigens, CD
  • Cancer Vaccines
  • Integrin alpha Chains
  • alpha E integrins
  • Sialyltransferases
  • beta-galactoside alpha-2,3-sialyltransferase
  • Neuraminidase

Associated data

  • ClinicalTrials.gov/NCT00576537
  • ClinicalTrials.gov/NCT00576641