CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy
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Fenne L. Komdeur1,*, Maartje C.A. Wouters1,2,*, Hagma H. Workel1, Aline M. Tijans1, Anouk L.J. Terwindt1, Kim L. Brunekreeft1, Annechien Plat1, Harry G. Klip1, Florine A. Eggink1, Ninke Leffers1, Wijnand Helfrich3, Douwe F. Samplonius3, Edwin Bremer3, G. Bea A. Wisman1, Toos Daemen2, Evelien W. Duiker4, Harry Hollema4, Hans W. Nijman1,#, Marco de Bruyn1,#
1University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands
2University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, The Netherlands
3University of Groningen, University Medical Center Groningen, Department of Surgery, The Netherlands
4University of Groningen, University Medical Center Groningen, Department of Pathology, The Netherlands
*These authors have contributed equally to this work
#MB and HWN share senior authorship
Hans W. Nijman, email: firstname.lastname@example.org
Keywords: tumor-infiltrating lymphocytes, high-grade serous ovarian cancer, CD103, TGF-β, cancer immunotherapy
Received: May 06, 2016 Accepted: September 02, 2016 Published: September 16, 2016
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+ TCRαβ+ CD8αβ+ 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 TGFβR1-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.
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