Highlights
- •NK cells and cytotoxic T cells infiltrate poorly into cholangiocarcinoma.
- •Regulatory T cells accumulate in cholangiocarcinoma.
- •PD1, CTLA4 and GITR are over-expressed on tumor-infiltrating T cells in cholangiocarcinoma.
- •Blocking PD1 or CTLA4 or stimulating GITR enhances effector functions of tumor-infiltrating T cells in cholangiocarcinoma.
Background & Aims
Cholangiocarcinoma is an aggressive hepatobiliary malignancy originating from biliary
tract epithelium. Whether cholangiocarcinoma is responsive to immune checkpoint antibody
therapy is unknown, and knowledge of its tumor immune microenvironment is limited.
We aimed to characterize tumor-infiltrating lymphocytes (TILs) in cholangiocarcinoma
and assess functional effects of targeting checkpoint molecules on TILs.
Methods
We isolated TILs from resected tumors of patients with cholangiocarcinoma and investigated
their compositions compared with their counterparts in tumor-free liver (TFL) tissues
and blood, by flow cytometry and immunohistochemistry. We measured expression of immune
co-stimulatory and co-inhibitory molecules on TILs, and determined whether targeting
these molecules improved ex vivo functions of TILs.
Results
Proportions of cytotoxic T cells and natural killer cells were decreased, whereas
regulatory T cells were increased in tumors compared with TFL. While regulatory T
cells accumulated in tumors, the majority of cytotoxic and helper T cells were sequestered
at tumor margins, and natural killer cells were excluded from the tumors. The co-stimulatory
receptor GITR and co-inhibitory receptors PD1 and CTLA4 were over-expressed on tumor-infiltrating
T cells compared with T cells in TFL and blood. Antagonistic targeting of PD1 or CTLA4
or agonistic targeting of GITR enhanced effector molecule production and T cell proliferation
in ex vivo stimulation of TILs derived from cholangiocarcinoma. The inter-individual variations
in TIL responses to checkpoint treatments were correlated with differences in TIL
immune phenotype.
Conclusions
Decreased numbers of cytotoxic immune cells and increased numbers of suppressor T
cells that over-express co-inhibitory receptors suggest that the tumor microenvironment
in cholangiocarcinoma is immunosuppressive. Targeting GITR, PD1 or CTLA4 enhances
effector functions of tumor-infiltrating T cells, indicating that these molecules
are potential immunotherapeutic targets for patients with cholangiocarcinoma.
Lay summary
The defense functions of immune cells are suppressed in cholangiocarcinoma tumors.
Stimulating or blocking “immune checkpoint” molecules expressed on tumor-infiltrating
T cells can enhance the defense functions of these cells. Therefore, these molecules
may be promising targets for therapeutic stimulation of immune cells to eradicate
the tumors and prevent cancer recurrence in patients with cholangiocarcinoma.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 10, 2019
Accepted:
May 29,
2019
Received in revised form:
May 29,
2019
Received:
October 10,
2018
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
