Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A complementary DNA (cDNA) library from a cloned subline (CD-11) of a well differentiated human pancreatic tumor cell line, HPAF, was subjected to differential screening using single stranded cDNA probes synthesized from mRNA of the well differentiated cell clone CD-11 and a poorly differentiated pancreatic tumor cell line, Panc 1. A cDNA clone (PD-1) was identified which had an insert of 626 base pairs (bp). PD-1 cDNA hybridized to a transcript of about 650 bp on Northern blot analysis, suggesting that the cDNA was close to full length. Densitometric analysis of Northern blots showed that a well differentiated pancreatic tumor line had a 5-fold higher PD-1 expression as compared to the poorly differentiated line, Panc 1. Nucleotide sequence analysis of the PD-1 cDNA and its deduced amino acid sequence showed an open reading frame of 399 bp. In addition to the open reading frame, the sequence had a 5' untranslated region of 61 bp and a 3' untranslated tail of 147 bp. The nucleotide sequence did not show any significant homology to any other sequence in the GENBANK or EMBL databases; however, the translated protein showed 35% homology to bacterial ribosomal proteins over 112 amino acids. Sequence analysis of the PD-1 cDNA and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of its in vitro transcription/translation product suggest that this gene encoded a protein of 16,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation and characterization of a complementary DNA (PD-1) differentially expressed by human pancreatic ductal cell tumors. 179 33

Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.
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PMID:PD-L2 is a second ligand for PD-1 and inhibits T cell activation. 1122 27

We describe here a newly identified member of the human B7 family, designated B7 homolog 3 (B7-H3), that shares 20-27% amino acid identity with other B7 family members. B7-H3 mRNA is not detectable in peripheral blood mononuclear cells, although it is found in various normal tissues and in several tumor cell lines. Expression of B7-H3 protein, however, can be induced on dendritic cells (DCs) and monocytes by inflammatory cytokines and a combination of phorbol myristate acetate (PMA) + ionomycin. Soluble B7-H3 protein binds a putative counter-receptor on activated T cells that is distinct from CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), inducible costimulator (ICOS) and PD-1. B7-H3 costimulates proliferation of both CD4+ and CD8+ T cells, enhances the induction of cytotoxic T cells and selectively stimulates interferon gamma (IFN-gamma) production in the presence of T cell receptor signaling. In contrast, inclusion of antisense B7-H3 oligonucleotides decreases the expression of B7-H3 on DCs and inhibits IFN-gamma production by DC-stimulated allogeneic T cells.Thus, we describe a newly identified costimulatory pathway that may participate in the regulation of cell-mediated immune responses.
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PMID:B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. 1122 28

B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.
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PMID:Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 1215 31

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.
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PMID:Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 1221 88

B7-H1 is a recently identified member of the B7 family molecules. Upon ligation to its receptors on T cells it regulates activation and differentiation of T cells. B7-H1 preferentially costimulates IL-10 production in resting T cells and further induces the apoptosis of activated T cells. PD-1 is a receptor of B7-H1 and is shown to mediate the inhibition of activated T cell response, presumably by inhibiting cell cycle progression. The expression of B7-H1 protein is limited to macrophage lineage of cells in normal tissues, although its mRNA transcription is found in a broad range of tissues. In contrast, B7-H1 is abundant in various human cancers. The tumor-associated B7-H1 increases apoptosis of antigen specific T cells, leading to growth of immunogenic tumor growth in vivo. Current data suggest that B7-H1 regulates the organ-specific tolerance in normal tissue and may contribute to immune evasion by cancers. Selective manipulation of B7-H1 pathway thus aids in the design of new regimens in the treatment of human autoimmune disease and the control of malignant cancers.
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PMID:B7-H1 pathway and its role in the evasion of tumor immunity. 1272 64

B7H1 (PDL1) and B7DC (PDL2) are two new members of the B7 family that can interact with PD-1, a putative negative regulator for immune function. Recent studies have provided evidence for inhibitory functions of both members via PD-1. Meanwhile, compelling evidence exists for costimulatory function of both members. Here we demonstrate that expression of B7DC on the tumor cells promotes CD8 T cell-mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity. Moreover, B7DC binds to PD-1(-/-) cells and enhances T cell killing in a PD-1-independent mechanism. Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.
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PMID:B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism. 1281 Jun 90

Although increased circulating tumor antigen-specific CD8(+) T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the K(b)-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express K(b) in response to IFN-gamma, they were poorly recognized by primed 2C/RAG2(-/-) T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-gamma-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2(-/-)/PD-1(-/-) T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2(-/-)/PD-1(-/-) T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8(+) T cells in the tumor microenvironment.
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PMID:PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. 1487 49

The B7 family of T cell costimulatory molecules has recently acquired several new members. Some of these are activating while others are inhibitory. In this review, we will focus on the novel inhibitory pathways with particular emphasis on the PD-1:PD-L pathway. Understanding the mechanisms of these pathways has implications for development of novel treatment strategies for autoimmune disease, transplantation, tumor immunotherapy, and vaccine development.
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PMID:The roles of the new negative T cell costimulatory pathways in regulating autoimmunity. 1514 22

New members of the B7 family have been recently described as regulators of T cell activation and function. Butyrophilin (BT) has also been related to the B7 family by sequence similarity analyses. We present a new subfamily called BT3, which belongs to the B7/BT family. The BT3 subfamily comprises three members (BT3.1,.2 and.3) that exhibit 95% identity and form a monophylogenetic group along with the BT-related members. High expression levels of BT3 transcripts were detected in lymphoid tissues (mainly spleen, lymph node and PBL). Using anti-BT3 mAb we could demonstrate BT3 expression on immune cells including T, B and NK cells, monocytes and dendritic cells as well as hematopoietic precursors and some tumor cell lines. As described earlier for PDL-1 and ICOS-L, BT3 molecules are expressed on endothelial cells and up-regulated upon activation by IFN-gamma or TNF-alpha. The BT3.1 counter-receptor (BT3.1-R) was analyzed by means of binding experiments using BT3.1-Ig soluble protein. The BT3.1-R is not CD28, CTLA-4, ICOS, PD-1 or BTLA and seems restricted to some T cell and hematopoietic cell lines. Altogether, these data describe new members of the B7/BT family that may play a role in regulation of the immune response.
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PMID:Frontline: Characterization of BT3 molecules belonging to the B7 family expressed on immune cells. 1525 5


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