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

Abstract

// Fenne L. Komdeur 1, * , Maartje C.A. Wouters 1, 2, * , Hagma H. Workel 1 , Aline M. Tijans 1 , Anouk L.J. Terwindt 1 , Kim L. Brunekreeft 1 , Annechien Plat 1 , Harry G. Klip 1 , Florine A. Eggink 1 , Ninke Leffers 1 , Wijnand Helfrich 3 , Douwe F. Samplonius 3 , Edwin Bremer 3 , G. Bea A. Wisman 1 , Toos Daemen 2 , Evelien W. Duiker 4 , Harry Hollema 4 , Hans W. Nijman 1, # , Marco de Bruyn 1, # 1 University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands 2 University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, The Netherlands 3 University of Groningen, University Medical Center Groningen, Department of Surgery, The Netherlands 4 University 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 Correspondence to: Hans W. Nijman, email: h.w.nijman@umcg.nl 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 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+ 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.