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

TY - JOUR

T1 - HLA-Restricted CTL That Are Specific for the Immune Checkpoint Ligand PD-L1 Occur with High Frequency in Cancer Patients

AU - Munir, Shamaila

AU - Andersen, Gitte Holmen

AU - Met, Özcan

AU - Donia, Marco

AU - Frøsig, Thomas Mørch

AU - Larsen, Stine Kiaer

AU - Klausen, Tobias Wirenfeldt

AU - Svane, Inge Marie

AU - Andersen, Mads Hald

PY - 2013/3/15

Y1 - 2013/3/15

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.can-12-3507

DO - 10.1158/0008-5472.can-12-3507

M3 - Journal article

C2 - 23328583

SN - 0008-5472

VL - 73

SP - 1764

EP - 1776

JO - Cancer Research

JF - Cancer Research

IS - 6

ER -