HLA-restricted CTL That Are Specific for the Immune Checkpoint Ligand PD-L1 Occur With High Frequency in Cancer Patients

Cancer Res. 2013 Mar 15;73(6):1764-76. doi: 10.1158/0008-5472.CAN-12-3507. Epub 2013 Jan 17.

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.

MeSH terms

  • B7-H1 Antigen / metabolism*
  • Case-Control Studies
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • HLA Antigens / immunology*
  • Humans
  • Neoplasms / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • HLA Antigens