Negative Regulation of T-Cell Function by PD-1

Zha, Yuan Yuan; Blank, Christian; Gajewski, Thomas F.

doi:10.1615/critrevimmunol.v24.i4.10

Cited by 79 publications

(55 citation statements)

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“…In contrast to CTLA-4, CD-28, and ICOSwhich are all obligate disulfide-linked homodimers-PD-1 is monomeric, both in solution and on the cell surface (14). The cytoplasmic region for PD-1 contains an immunoreceptor tyrosine -based inhibitory motif and an immunoreceptor tyrosine -based switch motif, indicating a negative regulatory function (14). Cell surface expression of PD-1 has been observed on activated T cells, stimulated macrophages, and mature dendritic cells (7).…”

Section: Discussionmentioning

confidence: 90%

“…The broad distribution of these ligands suggests that the PD-1/B7-H1/B7-DC family may regulate immune responses in both lymphoid and nonlymphoid organs (6). In addition, compared with other B7 costimulatory members, PD-1 is expressed at a relatively late phase following T cell activation, suggesting that the PD-1 pathway may primarily function at sites of inflammation in peripheral organs (14). In vitro and in vivo studies show that engagement of PD-1 by B7-H1 inhibits T cell proliferation, survival, or function, whereas blockade of PD-1 promotes the generation of autoreactive T cells as well as greater autoantibody production (14).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, compared with other B7 costimulatory members, PD-1 is expressed at a relatively late phase following T cell activation, suggesting that the PD-1 pathway may primarily function at sites of inflammation in peripheral organs (14). In vitro and in vivo studies show that engagement of PD-1 by B7-H1 inhibits T cell proliferation, survival, or function, whereas blockade of PD-1 promotes the generation of autoreactive T cells as well as greater autoantibody production (14). In addition, PD-1 -deficient mice develop a lupus-like proliferative arthritis and glomerulonephritis that is accompanied by dilated cardiomyopathy secondary to T and B cell dysregulation (14).…”

Section: Discussionmentioning

confidence: 99%

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PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma

Thompson¹,

Dong

Lohse³

et al. 2007

Clinical Cancer Research

508

358

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Purpose: B7-H1 is expressed by clinically aggressive forms of renal cell carcinoma (RCC) and predicts adverse outcome. B7-H1 is known to impair host immunity via interaction with the Programmed Death-1 (PD-1) receptor, which is expressed by activated Tcells. Levels of immune cells expressing PD-1 (PD-1 + ) in clinical RCC tumors have not been evaluated. Thus, we tested whether immune cell PD-1expression is observed within aggressive RCC tumors. Experimental Design: Between 2000 and 2003, 267 patients underwent nephrectomy at our institution for clear cell RCC and had fresh-frozen tissue available for review. These RCC specimens were immunostained using anti^PD-1 (clone MIH4) and outcome analyses were conducted.Results: Mononuclear immune cell infiltration was observed in 136 (50.9%) specimens. PD-1 + immune cells were present in 77 of these 136 (56.6%) tumors. In contrast, RCC tumor cells did not express PD-1. Patients with PD-1 + immune cells were significantly more likely to harbor B7-H1 + tumor cells (P < 0.001), larger tumors (P = 0.001), and tumors of higher nuclear grade (P = 0.001). Likewise, intratumoral PD-1 + immune cells were associated with advanced tumor-node-metastasis stage (P = 0.005), coagulative tumor necrosis (P = 0.027), and sarcomatoid differentiation (P = 0.008). With a median follow-up of 2.9 years, 52 patients died from RCC. Univariately, patients with PD-1 + immune cells were at significant risk of cancer-specific death compared with PD-1 À patients (risk ratio, 2.24; P = 0.004). Conclusions: Levels of immune cells expressing PD-1were increased in patients with high-risk RCC tumors. Interactions between immune cell PD-1and B7-H1may promote cancer progression by contributing to immune dysfunction in patients with RCC.Renal cell carcinoma (RCC) is an immunogenic tumor that characteristically harbors abundant infiltrating lymphocytes (1). Several reports, however, indicate that lymphocytes within RCC tumors are often rendered dysfunctional (2 -4). Thus, it seems that RCC tumors possess a potent regional ability to impair host antitumor immunity. Elucidating mechanisms responsible for immune dysfunction within the tumor microenvironment may prove useful to improve immunotherapeutic approaches for the treatment of RCC.The Programmed Death-1 (PD-1) receptor was first described in 1992 (5) as a member of the B7 family of costimulatory molecules that modulate T cell antigen-specific receptor signaling and govern T cell activation, inactivation, and survival (6). Membranous expression of the PD-1 glycoprotein has been described in association with activated T cells, B cells, and mature dendritic cells (7). Murine studies indicate that PD-1 functions as a negative regulator of immune responses, as is supported by the development of autoimmune glomerulonephritis, arthritis, and cardiomyopathy in PD-1 knockout mice (8).One known ligand for PD-1, B7-H1 (PD-L1, CD274), has been extensively studied in patients with RCC. We have reported that B7-H1 is aberrantly expressed by both primary and me...

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma

Thompson¹,

Dong

Lohse³

et al. 2007

Clinical Cancer Research

508

358

View full text Add to dashboard Cite

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“…[3][4][5][6]. Interaction of B7.1 (CD80) and B7.2 (CD86) with CD28 was the first of these receptor ligand pairs to be discovered, followed by studies showing that CTLA4 (CD152) could also engage B7.1 and B7.2, but to initiate negative, rather than positive, signaling in activated T cells (reviewed in Ref.…”

mentioning

confidence: 99%

B7 Costimulation Is Critical for Host Control of Chronic Mycobacterium tuberculosis Infection

Bhatt

Uzelac

Mathur

et al. 2009

The Journal of Immunology

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Although much is understood regarding the role of B7/CD28 family of costimulatory molecules in regulating host resistance in the context of several pathogens, analogous information with Mycobacterium tuberculosis is lacking. To address the requirements of B7-mediated costimulation in host resistance against tuberculosis, mice deficient in both B7.1 and B7.2 (B7DKO) were aerosol infected with M. tuberculosis Erdman and disease progression was monitored. We report herein that B7DKO mice are initially able to contain the bacterial load in the lung, but exhibit enhanced susceptibility during chronic infection. Despite the early control of bacterial replication, B7DKO mice essentially start off with compromised Th1 immunity and slower granulomatous response in the lung, characterized by markedly reduced lymphocytic infiltration. As the infection progresses from acute phase to the chronic phase, the nascent granulomas in the B7DKO lungs never fully achieve the architecture of granulomas developing in wild-type mice. Instead, lesions spread progressively to involve much of the lung in the B7DKO mice, ultimately leading to necrosis. Thus, early control of M. tuberculosis growth in the lung can occur in the absence of B7 costimulation and is less dependent on Th1 immunity and formation of a granulomatous structure. However, B7 costimulation is critical for long-term containment of infection within lung granulomas. These findings suggest that the use of costimulation-based immunomodulators may have significant repercussions on the induction of host protective immunity against tuberculosis.

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“…Arguably, the most important of these is PD-L1/B7-H1, which engages the inhibitory receptor on activated T cells called PD-1 (17). In contrast to the ligands for the alternative inhibitory receptor CTLA-4, PD-L1 can be expressed directly on tumor cells.…”

Section: Inhibitory Ligands: the Example Of Pd-l1mentioning

confidence: 99%

Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment

Gajewski

2006

Clinical Cancer Research

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The continually growing list of defined tumor antigens is broadening the potential applicability of tumor antigen-targeted cancer therapies. Although cancer vaccines and adoptive T-cell transfer have been shown to increase the frequency of circulating tumor antigen-specific Tcells, these approaches cause clinical responses in a few patients. In melanoma, approximately one third of metastatic lesions contain activated T cells, including those specific for tumor antigens, arguing that the priming phase has occurred already in such individuals even without vaccination. These observations indicate that tumor resistance to immune destruction may dominate in many instances, arguing for a thorough analysis of the melanoma tumor microenvironment in individual patients. Recent work has suggested that T-cell anergy, the influence of CD4 + CD25 + regulatory T cells, the expression of inhibitory ligands, such as PD-L1, and the activity of nutrient-catabolizing enzymes, such as indoleamine 2,3-dioxygenase, may be involved. Preclinical murine models have shown that interfering with each of these processes can translate into T-cell^mediated tumor control. Importantly, each of these targets is amenable to clinical manipulation. Clinical translation of these approaches to counter negative regulation of antitumor immunity should receive high priority.

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Negative Regulation of T-Cell Function by PD-1

Cited by 79 publications

References 0 publications

PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma

PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma

B7 Costimulation Is Critical for Host Control of Chronic Mycobacterium tuberculosis Infection

Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment

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