Involvement of PD-L1 on Tumor Cells in the Escape from Host Immune System and Tumor Immunotherapy by PD-L1 Blockade

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-09, Vol.99 (19), p.12293-12297
• Main Authors: Iwai, Yoshiko, Ishida, Masayoshi, Tanaka, Yoshimasa, Okazaki, Taku, Honjo, Tasuku, Minato, Nagahiro
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antigen presenting cells; Antigens, Surface; Apoptosis Regulatory Proteins; B7-1 Antigen; B7-H1 Antigen; Biological Sciences; Blood Proteins; Cells; Immunity; Immunotherapy; Inoculation; Ligands; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Nude; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; Peptides - antagonists & inhibitors; Peptides - genetics; Peptides - immunology; Programmed Cell Death 1 Receptor; Proteins - immunology; Receptors; Self Tolerance; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; Transfection; Tumor cell line; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.192461099

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.