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

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 tumorspecific 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.Key words: RCC; PD-L1; PD-1; B7-H1; melanoma Although the prognosis for patients with advanced solid tumors still remains poor, 1 a number of promising approaches, such as cancer immunotherapy, have been developed over the past decade. However, it is still an unsolved question why existing tumor-specific T cells in cancer patients fail to effectively prevent tumor progression. Inefficient T cell stimulation, either due to the absence of efficient antigen-presentation and costimulation or due to the presence of coinhibitory molecules, may contribute to this phenomenon.Data from animal models showing that CD8 1 T cells can lead to regression and rejection of solid tumors, and metastases 2 were reproduced with human cancer patients in clinical studies only partially. [3][4][5][6] Despite the fact that tumor-specific T cells can be expanded and transferred effectively and thus survive and localize into tumors, 7,8 tumor growth is not always controlled.It appears that the microenvironment of cancers protects tumor cells from immune destruction. 9,10 Increasing appreciation of costimulation (via CD28 or ICOS) and coinhibition (...

Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma

“…Many groups of investigators have reported that blockade of the PD-1/PD-L1 interaction promotes tumor immunity. [35][36][37] Conversely, there remains a problem regarding PD-1/PD-L1 blockade because of the possible expansion of poorly immunogenic cells. 38 Further studies may be required to clarify the therapeutic effect of PD-1/PD-L1 blockade in malignant melanoma models and clinical trials.…”

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

“…T cells become progressively more nonresponsive as they express additional inhibitory receptors (9). Tumor-infiltrating T cells may also be functionally inert, due in part to the expression of PD-1 along with other inhibitory receptors (10,11). In multiple syngeneic mouse tumor models, blockade of PD-1 or its ligands promotes antitumor activity (12)(13)(14); anti-PD-1 activity in vivo can be enhanced by combination with antibodies to other T-cell negative regulators, such as CTLA-4 and LAG-3 (15)(16)(17).…”

“…PD-L1 is expressed by many human tumors, including melanoma, lung, and kidney (10,18,19). PD-L1 engagement of PD-1 may be one mechanism whereby tumors evade immunosurveillance by directly limiting effector T-cell activity.…”

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

“…Antibodies that block the interaction between PD-L1 and its cognate receptors can relieve PD-L1-dependent immunosuppressive effects in vitro, enhancing the cytotoxic activity of antitumor T cells (19). Based in part on these observations, anti-PD-L1 antibodies could be used therapeutically to enhance antitumor immune responses in patients with cancer.…”