Format

Send to

Choose Destination
Oncoimmunology. 2016 Oct 7;5(12):e1240859. doi: 10.1080/2162402X.2016.1240859. eCollection 2016.

Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma.

Author information

1
Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center , Heidelberg, Germany.
2
BioNTech Diagnostics GmbH , Mainz, Germany.
3
Department of Pathology, Heidelberg University Hospital , Heidelberg, Germany.
4
Division of Theoretical Systems Biology, German Cancer Research Center and BioQuant Center, University of Heidelberg , Heidelberg, Germany.
5
Department of General, Visceral and Transplantation Surgery , Heidelberg University Hospital, Heidelberg, Germany.
6
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.
7
TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University , Mainz, Germany.
8
Division of Applied Stem Cell Biology, National Center for Tumor Diseases , Heidelberg, Germany.
9
Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg , Germany and HI-STEM gGmbH , Heidelberg, Germany.
10
National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Hospital , Heidelberg, Germany.
11
Department of Dermatology and National Center for Tumor Diseases, Heidelberg University Hospital , Heidelberg, Germany.
12
TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany; BioNTech AG, Mainz, Germany.
13
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.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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 of in vitro expanded T-cell cultures. Parallel studies were performed on tumor-infiltrating lymphocytes (TIL) from 44 patients with metastatic melanoma.

RESULTS:

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 vitro expansion of TILs was equally efficient for PDA and melanoma, resulting in T-cell cultures displaying HLA class I-restricted reactivity against autologous tumor cells.

CONCLUSIONS:

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.

KEYWORDS:

Adoptive T-cell therapy; T-cell receptor (TCR) repertoire; pancreatic ductal adenocarcinoma; tertiary lymphoid structures; tumor-infiltrating lymphocytes

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center