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  • Open Access

Phenotype, function and T cell receptor repertoire of tumor-infiltrating lymphocytes in patients with pancreatic ductal adenocarcinoma

  • 1,
  • 1,
  • 2,
  • 3,
  • 3,
  • 1 and
  • 1
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P44

https://doi.org/10.1186/2051-1426-3-S2-P44

  • Published:

Keywords

  • Melanoma
  • Deep Sequencing
  • Pancreatic Ductal Adenocarcinoma
  • Autologous Tumor Cell
  • Expansion Period

Background

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median survival of only about two years even in the 20% of patients that present early enough to be eligible for surgical resection and adjuvant chemotherapy. With this urgent medical need in mind, we are exploring the use of adoptive T cell transfer in patients with PDAC, as this therapy has shown remarkable clinical success in patients with advanced melanoma.

Results

Despite the notion that, different from melanoma, PDAC is a non-immunogenic tumor, we observe at least moderate (>150 CD3+cells/mm2) T cell infiltration in 60% of patient biopsies analyzed by immunohistochemistry (n=66). Flow cytometric analysis shows that tumor-infiltrating T lymphocytes (TILs) predominantly display an activated effector memory phenotype with signs of exhaustion or prolonged antigen exposure, such as high PD1 (n≥30).

Upon in vitro culture TILs can be expanded from 85% of PDAC patients (n=96) and show growth capacity and phenotypes similar to melanoma patient TIL (n=62). The majority of tested PDAC TIL cultures produce IFN-γ in response to autologous tumor cells in an MHC-I dependent manner, but cross-reactivity and a low response magnitude are common observations.

In order to gain insight into the original tumor-reactivity of TILs before expansion, we studied the T cell receptor (TCR) repertoire by deep sequencing and made the following observations: the TIL TCR repertoire is i) distinct from the broad repertoire observed in the blood; ii) usually dominated by large T cell clones, possibly due to in situ expansion after tumor-antigen encounter; and iii) in most patients not maintained during the TIL expansion period, likely leading to a loss of important T cell clones and a shift in tumor-reactivity in the TILs available for patient treatment after in vitro expansion.

Deep sequencing of the TCR repertoire in combination with TCR cloning provides us with a tool to study TIL reactivity directly ex vivo and to ‘rescue’ TIL-TCRs with valuable reactivities that could be reintroduced in the form of genetically engineered T cells. Whether PDAC TILs are reactive towards shared antigens and/or mutation-derived neo-antigens is currently being investigated based on exome and RNA sequencing data from a subset of patients.

Authors’ Affiliations

(1)
German Cancer Research Center (DKFZ), Heidelberg, Germany
(2)
3BioNTech Diagnostics GmBH, Mainz, Germany
(3)
Heidelberg University Hospital, Heidelberg, Germany

Copyright

© Poschke et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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