Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro

Christian Blank*, Juergen Kuball, Simon Voelkl, Heinz Wiendl, Bernd Becker, Bernhard Walter, Otto Majdic, Thomas F. Gajewski, Mathias Theobald, Reinhard Andreesen, Andreas Mackensen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

219 Citations (Scopus)

Abstract

Human tumors frequently escape immune destruction, despite the presence of cyototoxic T cells (CTL) recognizing tumor-associated antigens (TAA). We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses. To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumor-specific T cells. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma. Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on frozen sections from RCC and melanomas, but not on normal tissues. The corresponding inhibitory receptor of PD-L1, PD-1, revealed a higher expression on tumor-infiltrating lymphocytes than on peripheral blood lymphocytes (PBL) from melanoma patients upon specific antigen stimulation. Stimulation of PBL from healthy donors with peptide-loaded dendritic cells in the presence of anti-PD-L1 mAb altered neither the total T cell numbers after expansion, nor the percentage of peptide-specific CTL, when providing a T cell help by addition of cytokines. However, when stimulating TAA-specific CTL and T helper cells with Ag-pulsed dendritic cells in the absence of exogenous cytokines, PD-L1 blockade increased the cytokine production. Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor. In summary, our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominately in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion.

Original languageEnglish
Pages (from-to)317-327
Number of pages11
JournalInternational Journal of Cancer
Volume119
Issue number2
DOIs
Publication statusPublished - 15 Jul 2006

Keywords

  • B7-H1
  • Melanoma
  • PD-1
  • PD-L1
  • RCC

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