A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application

Okazaki, Taku; Chikuma, Shunsuke; Iwai, Yoshiko; Fagarasan, Sidonia; Honjo, Tasuku

doi:10.1038/ni.2762

Cited by 802 publications

(640 citation statements)

References 92 publications

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“…The latter also suggests that stable PD-1 expression might strictly correlate with the strength of antigen-stimulation, which is possibly lower in latent than in active chronic infections. This idea would be well in line with the concept that PD-1 serves as a rheostat following strong T-cell stimulation 61 . Moreover, several studies in active chronic infections established links between the magnitude of T-cell stimulation (or TCR avidity) and T-cell fate.…”

Section: Infections Which Show a Latent Phase (For Example Epstein-bamentioning

confidence: 54%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

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Section: Infections Which Show a Latent Phase (For Example Epstein-bamentioning

confidence: 54%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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“…SHP-2 then interferes with various aspects of T-cell function, including proliferation and cytokine production (5). In this manner, PD-1 is thought to maintain a balance between T-cell effector function and protection against excessive damage of peripheral tissues during infection (6).…”

Section: Introductionmentioning

confidence: 99%

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

Webb

Milne

Nelson

2015

Cancer Immunology Research

165

141

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a E (CD103)b 7 is a TGFb-regulated integrin that mediates retention of lymphocytes in peripheral tissues by binding to E-cadherin expressed on epithelial cells. We recently reported that a E (CD103)b 7 specifically demarcates intraepithelial CD8 þ tumor-infiltrating lymphocytes (CD8 TIL) in ovarian cancer and that CD103 þ TIL have a surface profile consistent with an active effector phenotype (HLA-DR þ , Ki67 þ , and CD127 lo ). These findings led us to hypothesize that, over time, CD103-mediated retention of CD8 TIL within the tumor epithelium might result in chronic stimulation by tumor antigen, which in turn might lead to an exhausted phenotype. To investigate this possibility, we evaluated PD-1 expression in a large cohort of ovarian tumors (N ¼ 489) with known CD103 þ TIL content. PD-1 þ cells were present in 38.5% of high-grade serous carcinomas (HGSC), but were less prevalent in other histologic subtypes. PD-1 þ TIL were strongly associated with increased disease-specific survival in HGSC (HR, 0.4864; P ¼ 0.0007). Multicolor immunohistochemistry and flow cytometry revealed a high degree of PD-1 and CD103 coexpression, specifically within the CD8 TIL compartment. PD-1 þ CD103 þ CD8 TIL were quiescent when assessed directly ex vivo yet were capable of robust cytokine production after pharmacologic stimulation. Moreover, they showed negligible expression of additional exhaustion-associated markers, including TIM-3, CTLA-4, and LAG-3. Thus, as hypothesized, CD103 þ CD8 TIL express PD-1 and appear quiescent in the tumor microenvironment. However, these cells retain functional competence and demonstrate strong prognostic significance. We speculate that, after standard treatment, PD-1 þ CD103 þ CD8 TIL might regain functional antitumor activity, an effect that potentially could be augmented by immune modulation. Cancer Immunol Res; 3(8); 926-35. Ó2015 AACR.

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“…In contrast, the CD56 dim subset is largely represented in PB (approximately 90%) and is characterized by high surface expression of KIRs, high cytotoxic activity against tumor-and virus-infected targets, and rapid production of cytokines on receptor-mediated cell activation. 34,35 A constitutive or inducible expression of PD-1 has been detected in different cell populations, including T, B, and myeloid cells, 14,36 whereas little is known regarding PD-1 expression on NK cells to date. In human subjects it has been reported that NK cells from patients with multiple myeloma 37 or patients with posttransplantation lymphoproliferative disorders 38 can express low PD-1 levels.…”

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confidence: 99%

“…Importantly, targeting PD-1/PD-L1 interactions can also improve the efficacy of adoptive cell therapies in tumors or chronic viral infections. [11][12][13][14] In some instances PD-1 blockade has been shown to mediate tumor eradication, [15][16][17] resulting in impressive and highly encouraging clinical results. Indeed, accumulating data indicate that the administration of an mAb to PD-1, used alone or in combination with other drugs, might provide a highly successful therapeutic tool in different types of advanced tumors, including melanoma, lung cancer, and ovarian carcinoma.…”

mentioning

confidence: 99%

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Pesce

Greppi

Tabellini

et al. 2017

Journal of Allergy and Clinical Immunology

382

386

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Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

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A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application

Cited by 802 publications

References 92 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

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