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

C Blank, I Brown, AC Peterson, M Spiotto, Y Iwai… - Cancer research, 2004 - AACR
C Blank, I Brown, AC Peterson, M Spiotto, Y Iwai, T Honjo, TF Gajewski
Cancer research, 2004AACR
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 …
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 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-γ, they were poorly recognized by primed 2C/RAG2−/− T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-γ-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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