Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu+ (MCF-7Her2/neu) and Her2/neu- (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2/neu and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respectively (p < 0.05). Lysis was less than 5% when targets were treated with either the non-humanized mu4D5 mAb or control huIgG. Lysis of rhu4D5-coated MCF-7Her2/neu cells was inhibited by 80 % when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. Enhanced ADCC of MCF-7Her2/neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low-dose IL-2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumor cells in the presence of IL-2 also produced large amounts of IFN-gamma with concomitant up-regulation of cell-surface activation markers CD25 and CD69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene.
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PMID:Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. 1159 78

Heat shock proteins (HSPs) are shown to be strong immunoadjuvants, eliciting both innate and adaptive immune responses against cancers. HSP110 is related in sequence to HSP70 and is approximately 4-fold more efficient in binding to and stabilizing denatured protein substrates compared with HSP70. In the present study we evaluated the ability of a heat shock complex of HSP110 with the intracellular domain (ICD) of human HER-2/neu to elicit effective antitumor immune responses and to inhibit spontaneous mammary tumors in FVB-neu (FVBN202) transgenic mice. The HSP110-ICD complex was capable of breaking tolerance against the rat neu protein and inhibiting spontaneous mammary tumor development. This vaccine induced ICD-specific IFN-gamma and IL-4 production. Depletion studies revealed that CD8(+) T cells were involved in protection against challenge with mouse mammary tumors, whereas CD4(+) T cells revealed partial protection. Increased IgG2a Ab titer in the sera of tumor-free animals after vaccination and elevated CD4(+) CD25(+) regulatory T cells in the PBL of tumor-bearing animals suggested that IFN-gamma-producing Th1 cells may be responsible for partial protection of CD4(+) T cells against the mammary tumor challenge, whereas CD4(+)CD25(+) regulatory T cells (Th2 cells) may suppress the antitumor immune responses. Together, these results suggest that HSP110-ICD complex can elicit effective IFN-gamma-producing T cells against spontaneous mammary tumors and that up-regulation of CD4(+) CD25(+) regulatory T cells may prevent complete eradication of the tumor following immunotherapy.
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PMID:HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice. 1453 Mar 26

Regulatory T (Treg) cell activity has been observed in anti-tumor and autoimmunity since the 1970s. Functional and molecular characterization of Treg cells has been made possible by the recent association of cell markers, such as CD25, CTLA-4, GITR, and Foxp3 gene product, with immunoregulatory activity. Here the influence of Treg cells in both anti-tumor immunity and autoimmunity was measured in BALB/c mice. Depletion of CD4(+)CD25(+) Treg cells with CD25 mAb resulted in mammary tumor regression and increased susceptibility to thyroiditis. This in vivo priming to both tumor-associated antigens and self-thyroglobulin attests to the presence of otherwise undetectable immune effectors which are under negative regulation. Modulation of Treg cells is a powerful strategy in cancer therapy, but may potentiate autoimmune complications. Murine models exhibiting breakable tolerance to tumor-associated antigens, such as ErbB-2 (HER-2/ neu), and increased susceptibility to autoimmunity following Treg-cell depletion are being established to test new vaccination or therapeutic strategies involving Treg-cell modulation.
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PMID:Anti-tumor immunity and autoimmunity: a balancing act of regulatory T cells. 1461 Jun 19

A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8(+) T cell responses to a dominant peptide (RNEU(420-429)) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N-derived CD4(+)CD25(+) T cells. RNEU(420-429)-specific CD8(+) T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU(420-429)-specific CD8(+) T cells comparable to those generated from vaccinated FVB/N mice. Cyclophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4(+)CD25(+) T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8(+) T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination.
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PMID:Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. 1588 72

When CD4+ CD25+ regulatory T cells are depleted or inactivated for the purpose of enhancing antitumor immunity, the risk of autoimmune disease may be significantly elevated because these regulatory T cells control both antitumor immunity and autoimmunity. To evaluate the relative benefit and risk of modulating CD4+ CD25+ regulatory T cells, we established a new test system to measure simultaneously the immune reactivity to a tumor-associated antigen, neu, and an unrelated self-antigen, thyroglobulin. BALB/c mice were inoculated with TUBO cells expressing an activated rat neu and treated with anti-CD25 monoclonal antibody to deplete CD25+ cells. The tumors grew, then regressed, and neu-specific antibodies and IFN-gamma-secreting T cells were induced. The same mice were also exposed to mouse thyroglobulin by chronic i.v. injections. These mice produced thyroglobulin-specific antibody and IFN-gamma-secreting T cells with inflammatory infiltration in the thyroids of some mice. The immune responses to neu or thyroglobulin were greater in mice undergoing TUBO tumor rejection and thyroglobulin injection than in those experiencing either alone. To the best of our knowledge, this is the first experimental system to assess the concurrent induction and possible synergy of immune reactivity to defined tumor and self-antigens following reduction of regulatory T cells. These results illustrate the importance of monitoring immune reactivity to self-antigens during cancer immunotherapy that involves immunomodulating agents, and the pressing need for novel strategies to induce antitumor immunity while minimizing autoimmunity.
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PMID:Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4+ CD25+ regulatory T cell-depleted mice. 1616 27

A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. However, tumor regression in this model is transient and long-term cure is not achieved due to recurrence. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression. Therapy-induced reversion of immune suppression was transient since all three markers of suppression recovered rapidly and surpassed pretherapy levels by day 7 after treatment, resulting in tumor resurgence. Repeated treatment enhanced short-term tumor regression, but did not augment long-term survival. Serial long-term analysis demonstrated that although chronic stimulation enhanced the IFN-gamma response, this was countered by a parallel increase in Foxp3, TGFbeta, and IL-10 expression. Analysis of tumor-infiltrating T lymphocyte populations showed that the expression of Foxp3 and IL-10 was associated with CD4(+)CD25(+) T cells. Repeated treatment resulted in a progressive increase in tumor-infiltrating CD4(+)CD25(+)Foxp3(+) T suppressor cells establishing their role in long-term neutralization of antitumor activity. Analysis of tumor-infiltrating CD8(+) T cells demonstrated that although treatment enhanced IFN-gamma production, antitumor cytotoxicity was diminished. Monitoring of CD8(+) T cells that specifically recognized a dominant MHC class I her-2/neu peptide showed a dramatic increase in tetramer-specific CD8(+) T cells after the first treatment; however, continuous therapy resulted in the loss of this population. These results demonstrate that both enhanced suppressor activity and deletion of tumor-specific T cells are responsible for the progressive loss of efficacy that is associated with chronic immune therapy.
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PMID:Chronic immune therapy induces a progressive increase in intratumoral T suppressor activity and a concurrent loss of tumor-specific CD8+ T effectors in her-2/neu transgenic mice bearing advanced spontaneous tumors. 1675 76

Forkhead box protein P3 (FOXP3) contributes to a unique transcriptional signature and serves as a functional marker of CD4(+)CD25(+) natural regulatory T cells. Dysfunction of FOXP3 in human is associated with fatal autoimmune disease known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) or X-linked autoimmunity-allergic disregulation syndrome (XLAAD). FOXP3 also can act as a breast tumor suppressor of the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog (avian)) (Her2/neu) gene. While the suppressive functions of FOXP3 in maintaining the immune balance between tolerance and autoimmunity are obvious, the underlying molecular mechanism remains almost entirely undefined. Recent studies indicate that FOXP3 may form a dynamic superamolecular complex with a variety of molecular partners including transcription factors and enzymatic proteins to regulate transcription. How the FOXP3 ensemble changes in response to T-cell receptor signals and/or proinflammatory signal remains unclear although work from this laboratory has revealed its complexity. Structural information on FOXP3 complex may offer novel functional insights, as well as facilitate the development of rational means to modulate regulatory T-cell function in various human diseases.
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PMID:FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity. 1862 75

We have shown that neu transgenic mice are immunotolerant and that immunizations with dendritic cells (DC) pulsed with neu-derived antigens were not able to control tumor growth in these animals. We tested whether, by modulating the tumor microenvironment with Toll-like receptor ligands, it could be possible to induce the activation of antitumor responses in neu mice. Our results indicate that only intratumoral (i.t.) injections of CpG-ODN induce an antitumor response in neu mice. To target the CpG-ODN to the tumor site anywhere within the body, we chemically conjugated an anti-Her-2/neu monoclonal antibody (mAb) with CpG-ODN. The anti-neu-CpG hybrid molecule retained its ability to bind to Her-2/neu(+) tumors, activate DCs, and induce antitumor responses. Our results indicated that injections of anti-neu-CpG induced the rejection of primary tumors in 100% of BALB/c mice and only in approximately 30% of BALB-neuT mice. After challenging the BALB/c and BALB-neuT mice, we observed that BALB/c mice developed a protective memory response; in contrast, BALB-neuT mice succumbed to the challenge. After injections of anti-neu-CpG, T regulatory cells (T-reg) were drastically reduced at the tumor site, but a large number were still present in the lymphoid organs. When BALB-neuT mice were treated with anti-neu-CpG plus anti-GITR mAb, but not with anti-CD25 mAb, 100% of the BALB-neuT mice rejected the primary tumor and developed a protective memory response indicating the critical role of T-regs in regulating the repertoire against self antigens. Taken together, these results indicate that CpG-ODN-targeted therapy and depletion of T-regs optimally activate a primary response and generate a protective memory response against self-tumor antigens.
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PMID:Systemic targeting of CpG-ODN to the tumor microenvironment with anti-neu-CpG hybrid molecule and T regulatory cell depletion induces memory responses in BALB-neuT tolerant mice. 1879 41

Modulation of the immune system to amplify anti-tumor immunity carries the risk of developing autoimmune diseases, including hypothyroidism, as seen with cancer patients undergoing clinical trials for immunotherapeutic regimens. Although there is a tendency to view autoimmunity as a positive indicator for cancer immunotherapy, some autoimmune manifestations can be life-threatening and necessitate prolonged medical intervention or removal from trial. We have established murine test models to assess such risks by monitoring, simultaneously, the immune reactivity to tumor-associated rat erbB-2 (neu) and another self Ag, mouse thyroglobulin (mTg). We previously reported that in wild-type, thyroiditis-resistant BALB/c mice that underwent regression of neu(+) TUBO tumors following regulatory T cell (Treg) depletion, immune responses to rat neu and mTg with resultant autoimmune thyroiditis (EAT) were both enhanced. In this study, we tested the balance between tumor immunity and autoimmunity in neu-transgenic BALB NeuT female mice. First, growth and progression of neu(+) tumor were compared in neu tolerant mice treated with either CD25 mAb to deplete Tregs and/or DNA vaccination. Only Treg depletion followed by neu DNA vaccination abrogated tolerance to neu, resulting in complete regression of neu(+) tumors, as well as long-term protection from spontaneous tumorigenesis in 58% of mice. The risk of developing EAT was then assessed by incorporated mTg immunization with or without LPS as adjuvant. In mice with induced tumor regression, mTg response was enhanced with modest increases in EAT development. Therefore, tumor regression induced by Treg depletion and DNA vaccination can exacerbate autoimmunity, which warrants close monitoring during immunotherapy.
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PMID:Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity. 1938 Aug 36

Mouse mammary tumor virus-Neu (MMTV/neu) transgenic mice on an FVB-background (FVB-neuN) have increased numbers of myeloid derived suppressor cells (MDSCs) and regulatory T-cells (T-regs) in the spleen during mammary tumor induction and progression. Using this transgenic tumor model, we assessed the therapeutic activity of sunitinib, a multi-targeted, tyrosine kinase (TK) inhibitor and its effects on immune-regulatory cells. Our preliminary results show that sunitinib at 40mg/kg/day, p.o. (per os), delayed the time to tumor induction and reduced the incidence and growth of tumors in FVB-neuN mice. In association with its therapeutic activity, sunitinib reduced the absolute number of splenic T-reg cells (CD4(+)CD25(+)CD62L(+)) and MDSCs (CD11b(+)Gr1(+)) that were increased during tumor progression with less activity in mice with gross tumors. A significant decrease in the absolute number of splenic T-regs, dendritic cells (DCs), MDSCs and hematopoietic progenitors (Lin(-)Sca1(+)CD90(dull)) was observed following sunitinib treatment. The frequency of splenic T-regs and hematopoietic progenitors, but not MDSCs was also reduced by sunitinib treatment. Additionally immune-regulatory cytokines and enzymes were down regulated by sunitinib treatment, including TGFbeta and NOS2 in the spleen cells of sunitinib treated mice as compared to untreated tumor bearing (TB) mice. We conclude that sunitinib has therapeutic activity, in association with the down regulation of MDSCs and T-regs and has a trend towards the normalization of the inflammatory cytokine levels induced by tumor progression and growth. Based on these results, we suggest that sunitinib reduction of immune suppressive cells is a critical part of its adjuvant immune therapeutic activity.
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PMID:Therapeutic activity of sunitinib for Her2/neu induced mammary cancer in FVB mice. 1983 32


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