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

• Published in: International journal of cancer 2006-07, Vol.119 (2), p.317-327
• Main Authors: Blank, Christian, Kuball, Juergen, Voelkl, Simon, Wiendl, Heinz, Becker, Bernd, Walter, Bernhard, Majdic, Otto, Gajewski, Thomas F., Theobald, Mathias, Andreesen, Reinhard, Mackensen, Andreas
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antigens, CD - drug effects; Antigens, Differentiation - drug effects; Antineoplastic Agents - pharmacology; B7-1 Antigen - drug effects; B7-H1 Antigen; B7‐H1; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; CTLA-4 Antigen; Flow Cytometry; Gene Expression Regulation, Neoplastic; Host-tumor relations. Immunology. Biological markers; Humans; Immunohistochemistry; Kidney Neoplasms - drug therapy; Kidneys; Medical sciences; melanoma; Melanoma - drug therapy; Melanoma - metabolism; Nephrology. Urinary tract diseases; PD‐1; PD‐L1; RCC; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - metabolism; Tumor Cells, Cultured; Tumors; Tumors of the urinary system; Up-Regulation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.21775

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. © 2006 Wiley‐Liss, Inc.