CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy

Fenne L Komdeur, Maartje C A Wouters, Hagma H Workel, Aline M Tijans, Anouk L J Terwindt, Kim L Brunekreeft, Annechien Plat, Harry G Klip, Florine A Eggink, Ninke Leffers, Wijnand Helfrich, Douwe F Samplonius, Edwin Bremer, G Bea A Wisman, Toos Daemen, Evelien W Duiker, Harry Hollema, Hans W Nijman, Marco de Bruyn

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Abstract

CD103+ tumor-infiltrating lymphocytes (TIL) have been linked to specific epithelial infiltration and a prolonged survival in high-grade serous epithelial ovarian cancer (HGSC). However, whether these cells are induced as part of an ongoing anti-HGSC immune response or represent non-specifically expanded resident or mucosal lymphocytes remains largely unknown. In this study, we first confirmed that CD103+ TIL from HGSC were predominantly localized in the cancer epithelium and were strongly correlated with an improved prognosis. We further demonstrate that CD103+ TIL were almost exclusively CD3+ TCR alpha beta+ CD8 alpha beta+ CD4-T cells, but heterogeneously expressed T cell memory and differentiation markers. Activation of peripheral T cells in the presence of HGSC was sufficient to trigger induction of CD103 in over 90% of all CD8+ cells in a T cell receptor (TCR)-and TGF beta R1-dependent manner. Finally, CD103+ TIL isolated from primary HGSC showed signs of recent activation and dominantly co-expressed key immunotherapeutic targets PD-1 and CD27. Taken together, our data indicate CD103+ TIL in HGSC are formed as the result of an adaptive anti-tumor immune response that might be reactivated by (dual) checkpoint inhibition.

Original languageEnglish
Pages (from-to)75130-75144
Number of pages15
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - 15-Nov-2016

Keywords

  • tumor-infiltrating lymphocytes
  • high-grade serous ovarian cancer
  • CD103
  • TGF-beta
  • cancer immunotherapy
  • TUMOR-INFILTRATING LYMPHOCYTES
  • LYTIC GRANULE POLARIZATION
  • PROGNOSTIC-SIGNIFICANCE
  • ADOPTIVE IMMUNOTHERAPY
  • FAVORABLE PROGNOSIS
  • CD103 EXPRESSION
  • TGF-BETA
  • CARCINOMA
  • PROMOTES
  • LUNG

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