PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells.

Abstract

Although increased circulating tumor antigen-specific CD8(+) T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the K(b)-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express K(b) in response to IFN-gamma, they were poorly recognized by primed 2C/RAG2(-/-) T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-gamma-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2(-/-)/PD-1(-/-) T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2(-/-)/PD-1(-/-) T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8(+) T cells in the tumor microenvironment.

• Authors: Christian Blank, Ian Brown, Amy C Peterson, Mike Spiotto, Yoshiko Iwai, Tasuku Honjo, Thomas F Gajewski
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 3 Pg. 1140-5 (Feb 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 14871849 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antigens, Differentiation
• B7-1 Antigen
• B7-H1 Antigen
• Blood Proteins
• CTLA-4 Antigen
• CTLA4 protein, human
• Cd274 protein, mouse
• Ctla4 protein, mouse
• Membrane Glycoproteins
• Peptides
• Receptors, Antigen, T-Cell
• Interferon-gamma

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antigens, CD
• Antigens, Differentiation (immunology)
• B7-1 Antigen
• B7-H1 Antigen
• Blood Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• CD8-Positive T-Lymphocytes (immunology)
• CTLA-4 Antigen
• Interferon-gamma (pharmacology)
• Membrane Glycoproteins
• Mice
• Mice, Transgenic
• Neoplasms, Experimental (genetics, immunology)
• Peptides (antagonists & inhibitors, genetics, physiology)
• Receptors, Antigen, T-Cell (antagonists & inhibitors, genetics, immunology)
• Transduction, Genetic
• Up-Regulation (drug effects)