title: Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma.
abstract: The devastating prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDA) presents an urgent need for the development of therapeutic strategies targeting disseminated tumor cells. Until now, T-cell therapy has been scarcely pursued in PDA, due to the prevailing view that it represents a poorly immunogenic tumor.
  
  
  
  We systematically analyzed T-cell infiltrates in tumor biopsies from 127 patients with resectable PDA by means of immunohistochemistry, flow cytometry, T-cell receptor (TCR) deep-sequencing and functional analysis ofin vitroexpanded T-cell cultures. Parallel studies were performed on tumor-infiltrating lymphocytes (TIL) from 44 patients with metastatic melanoma.
  
  
  
  Prominent T-cell infiltrates, as well as tertiary lymphoid structures harboring proliferating T-cells, were detected in the vast majority of biopsies from PDA patients. The notion that the tumor is a site of local T-cell expansion was strengthened by TCR deep-sequencing, revealing that the T-cell repertoire in the tumor is dominated by highly frequent CDR3 sequences that can be up to 10,000-fold enriched in tumor as compared to peripheral blood. In fact, TCR repertoire composition in PDA resembled that in melanoma. Moreover,in vitroexpansion of TILs was equally efficient for PDA and melanoma, resulting in T-cell cultures displaying HLA class I-restricted reactivity against autologous tumor cells.
  
  
  
  The tumor-infiltrating T-cell response in PDA shows striking similarity to that in melanoma, where adoptive T-cell therapy has significant therapeutic impact. Our findings indicate that T-cell-based therapies may be used to counter disease recurrence in patients with resectable PDA.
authors.affiliation: Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Poschke
authors.affiliation: BioNTech Diagnostics GmbH , Mainz, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Faryna
authors.affiliation: Department of Pathology, Heidelberg University Hospital , Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center and BioQuant Center, University of Heidelberg , Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Flossdorf
authors.affiliation: Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lauenstein
authors.affiliation: Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hermes
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hinz
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hank
authors.affiliation: Division of Applied Stem Cell Biology, National Center for Tumor Diseases, Heidelberg, Germany; National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Ehrenberg
authors.affiliation: Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Volkmar
authors.affiliation: TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University , Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Loewer
authors.affiliation: Division of Applied Stem Cell Biology, National Center for Tumor Diseases , Heidelberg, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg , Germany and HI-STEM gGmbH , Heidelberg, Germany.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Sprick
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center and BioQuant Center, University of Heidelberg , Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg , Germany and HI-STEM gGmbH , Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Hospital , Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.affiliation: Department of Dermatology and National Center for Tumor Diseases, Heidelberg University Hospital , Heidelberg, Germany.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Hassel
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Strobel
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Büchler
authors.affiliation: TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany; BioNTech AG, Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
keywords: Adoptive T-cell therapy; T-cell receptor (TCR) repertoire; pancreatic ductal adenocarcinoma; tertiary lymphoid structures; tumor-infiltrating lymphocytes