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[Cancer Research 64, 1140-1145, February 1, 2004]
© 2004 American Association for Cancer Research

Immunology

PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells

Christian Blank1, Ian Brown1, Amy C. Peterson2, Mike Spiotto1, Yoshiko Iwai3, Tasuku Honjo3 and Thomas F. Gajewski1,2

1 Departments of Pathology and 2 Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, and 3 Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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 Kb-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 Kb 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.




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