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HLA-restricted CTL that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients.

Authors
  • Munir, Shamaila
  • Andersen, Gitte Holmen
  • Met, Özcan
  • Donia, Marco
  • Frøsig, Thomas Mørch
  • Larsen, Stine Kiaer
  • Klausen, Tobias Wirenfeldt
  • Svane, Inge Marie
  • Andersen, Mads Hald
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Mar 15, 2013
Volume
73
Issue
6
Pages
1764–1776
Identifiers
DOI: 10.1158/0008-5472.CAN-12-3507
PMID: 23328583
Source
Medline
License
Unknown

Abstract

PD-L1 (CD274) contributes to functional exhaustion of T cells and limits immune responses in patients with cancer. In this study, we report the identification of an human leukocyte antigen (HLA)-A2-restricted epitope from PD-L1, and we describe natural, cytolytic T-cell reactivity against PD-L1 in the peripheral blood of patients with cancer and healthy individuals. Notably, PD-L1-specific T cells were able not only to recognize and kill tumor cells but also PD-L1-expressing dendritic cells in a PD-L1-dependent manner, insofar as PD-L1 ablation rescued dendritic cells from killing. Furthermore, by incubating nonprofessional antigen-presenting cells with long peptides from PD-L1, we found that PD-L1 was rapidly internalized, processed, and cross-presented by HLA-A2 on the cell surface. Apparently, this cross-presentation was TAP-independent, as it was conducted not only by B cells but in addition by TAP-deficient T2-cells. This is intriguing, as soluble PD-L1 has been detected in the sera from patients with cancer. PD-L1-specific CTL may boost immunity by the killing of immunosuppressive tumor cells as well as regulatory cells. However, PD-L1-specific CTLs may as well suppress immunity by the elimination of normal immune cells especially PD-L1 expressing mature dendritic cells.

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