title: HLA-restricted CTL that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients.
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.
authors: Center for Cancer Immune Therapy, Department of Hematology and Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej, Herlev, Denmark.
authors: Shamaila
authors: S
authors: Munir
authors: Gitte Holmen
authors: GH
authors: Andersen
authors: Özcan
authors: Ö
authors: Met
authors: Marco
authors: M
authors: Donia
authors: Thomas Mørch
authors: TM
authors: Frøsig
authors: Stine Kiaer
authors: SK
authors: Larsen
authors: Tobias Wirenfeldt
authors: TW
authors: Klausen
authors: Inge Marie
authors: IM
authors: Svane
authors: Mads Hald
authors: MH
authors: Andersen
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D009369:Neoplasms / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D006680:HLA Antigens