Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy

Blank, Christian U.; Gajewski, Thomas F.; Mackensen, Andréas

doi:10.1007/s00262-004-0593-x

Cited by 539 publications

(413 citation statements)

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“…60 In addition, PD-L1 was reported to be expressed on a wide variety of murine and human tumors, either constitutively or upon exposure to IFN-g. 22,42,53,64 Tumor-associated PD-L1 has been shown in animal models to inhibit antitumoral T cell responses, 20 implying PD-L1 to play a pivotal role in tumor evasion from antitumor immune responses. 20,53,65 Furthermore, it has been shown that activated T cells also express PD-L1, raising the possibility of self-restriction of an antitumor T cell response during the priming phase. 22,66 We thus addressed, in our study, the question at which stages and under which conditions of induction and effector phases of human tumor-specific T cell responses the addition of neutralizing anti-PD-L1 mAb might be beneficial.…”

Section: Discussionmentioning

confidence: 99%

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

Blank

Kuball

Voelkl

et al. 2006

Intl Journal of Cancer

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274

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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 (...

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Section: Discussionmentioning

confidence: 99%

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

Blank

Kuball

Voelkl

et al. 2006

Intl Journal of Cancer

Self Cite

274

201

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“…Taken together, these results suggest that T cells specific to mHA expressed by both tumor cells and healthy tissues of bone marrow-transplanted recipients might not be able to mediate antileukemia effect. This is particularly relevant if one considers the major importance of PD-L1 tumor cell expression in the phenomenon of immune evasion (47).…”

Section: Figurementioning

confidence: 99%

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

Rivas

Weatherly

Hazzan

et al. 2009

The Journal of Immunology

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In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient’s mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo. However, analysis of the gene expression profile of adapted CD4+ T cells revealed the specific coexpression of genes known to promote differentiation and function of Th1 effector cells as well as genes coding for proteins that control T cell activity, such as cell surface-negative costimulatory molecules and regulatory cytokines. Strikingly, blockade of negative costimulation abolished T cell adaptation and stimulated strong IFN-γ production and severe multiorgan wasting disease. Negative costimulation was also shown to control lethal LPS-induced toxic shock in mice with adapted T cells, as well as the capacity of adapted T cells to reject skin graft. Our results demonstrate that negative costimulation is the molecular mechanism used by CD4+ T cells to adapt their activity in response to persistent antigenic stimulation. The effector function of CD4+ T cells that have adapted to chronic Ag presentation can be activated by stimuli strong enough to overcome regulatory signals delivered to the T cells by negative costimulation.

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“…However, multiple regulatory mechanisms that blunt T cell function within the tumor microenvironment arise in tumors (27). Programmed death ligand 1 (PD-L1), an inhibitory molecule frequently upregulated on tumor cells, is one of the major immunological checkpoints contributing to tumor-immune escape (28) through the inhibition of T cell activation and promotion of apoptosis of DCs (29) and CD8 + T cells (30). In several clinical trials, blockade of programmed death-1 (PD-1) or PD-L1 resulted in enhanced T cell function and improved immune-mediated tumor control (31).…”

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confidence: 99%

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

Iraolagoitia

Spallanzani

Torres

et al. 2016

The Journal of Immunology

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Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8+ T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell–depleted mice exhibited a significantly higher frequency of SIY-specific CD8+ T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8+ T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell–depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.

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Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy

Cited by 539 publications

References 72 publications

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

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

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

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