Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vaccine immunotherapy must induce helper and cytotoxic cell-mediated immunity to generate the powerful antitumor immune responses needed to suppress cancer progression. We reported previously that a 16-amino acid peptide analogue derived from pigeon cytochrome c can bind broad ranges of MHC class II types and activate helper T cells in mice. To determine whether DNA encoding the Pan-MHC class II IA peptide (Pan-IA) can increase the efficacy of tumor suppression by DNA vaccine immunotherapy targeting tumor antigens, Pan-IA DNA was administered with ovalbumin (OVA) DNA to C57BL/6 mice bearing the OVA-expressing tumor cell line E.G7. Specific proliferative responses to and cytotoxic activities against OVA-expressing targets were induced in mice vaccinated with both OVA and Pan-IA DNA but not in those vaccinated with OVA DNA alone or control DNA plus Pan-IA DNA. Growth of E.G7 cells was suppressed only by combined vaccination with OVA and Pan-IA DNA, and tumors in five of the nine mice that received this combined vaccination were eradicated completely. In those mice, the frequency of CD8-positive T cells reactive with OVA(257-264) peptides in the context of H-2K(b) was significantly increased in the tumor site. Furthermore, immunofluorescent study of the inoculated tumors revealed increased accumulation of both CD4- and CD8-positive T cells producing IFN-gamma in the tumor only by this vaccine protocol. The data suggest that Pan-IA DNA can augment suppressive effects of DNA vaccines on tumor growth by increasing numbers of antigen-specific CTLs and helper T cells. This is the first study in which established tumors have been eradicated successfully by vaccination with DNA corresponding to CTL epitopes and helper T cell epitopes. Our animal model may contribute to the development of therapeutic DNA vaccines against cancer.
 ...
PMID:Deoxyribonucleic acid (DNA) encoding a pan-major histocompatibility complex class II peptide analogue augmented antigen-specific cellular immunity and suppressive effects on tumor growth elicited by DNA vaccine immunotherapy. 1463 22

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.
 ...
PMID:PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. 1487 49

IL-12 is a major activator of tumor-killing NK cells and CTL. IFN-gamma mediates most of the well-known immunological activities of IL-12. In this study, we report IFN-gamma-independent activities induced by therapeutic application of rIL-12 in restricting tumor growth and metastasis in the 4T1 murine mammary carcinoma model. IFN-gamma-deficient mice carrying 4T1 tumor exhibit no gross defect in the number of tumor-infiltrating lymphocytes but have exaggerated angiogenesis in the tumor. Administration of IL-12 is able to constrict blood vessels in the tumor in the absence of IFN-gamma, and retains certain therapeutic efficacy even when applied late during tumor progression. IL-12 exposure in vivo does not irreversibly alter the immunogenicity of the tumor. Finally, global gene expression analysis of primary tumors reveals IL-12-induced molecular patterns and changes, implicating a number of novel genes potentially important for IFN-gamma-independent immune responses against the tumor, for IL-12-mediated antiproliferation, antimetastasis, and antiangiogenesis activities.
 ...
PMID:Genome-wide analysis of molecular changes in IL-12-induced control of mammary carcinoma via IFN-gamma-independent mechanisms. 1503 23

The transforming rat Her-2/neu oncogene embedded into the genome of virgin transgenic BALB/c mice (BALB-neuT) provokes the development of an invasive carcinoma in each of their 10 mammary glands. i.m. vaccination with DNA plasmids coding for the extracellular and transmembrane domains of the protein product of the Her-2/neu oncogene started when mice already display multifocal in situ carcinomas temporarily halts neoplastic progression, but all mice develop a tumor by week 43. By contrast, progressive clearance of neoplastic lesions and complete protection of all 1-year-old mice are achieved when the same plasmids are electroporated at 10-week intervals. Pathological findings, in vitro tests, and the results from the immunization of both IFN-gamma and immunoglobulin gene knockout BALB-neuT mice, and of adoptive transfer experiments, all suggest that tumor clearance rests on the combination of antibodies and IFN-gamma-releasing T cells. These findings show that an appropriate vaccine effectively inhibits the progression of multifocal preneoplastic lesions.
 ...
PMID:Electroporated DNA vaccine clears away multifocal mammary carcinomas in her-2/neu transgenic mice. 1508 4

Effector T cells fall into two subpopulations based on cytokine-secretion. Type 1 cells secrete IFN-gamma, whereas type 2 cells secrete IL-4, IL-10, and GM-CSF. NKT cells represent a third subpopulation that secretes similar cytokines and have been associated with immunoregulation. Using the TS/A adenocarcinoma, we assessed the phenotype and kinetics of tumor-infiltrating lymphocytes (TIL) in mice challenged subcutaneously in the mammary region. Flow cytometric analysis shows that T cells do not infiltrate the primary tumor site until days 7-14 following tumor challenge. Both CD4 and CD8 TILs were predominantly CD44(High) and expressed CD25, CD69, and CD95 cell surface activation markers. Activated CD4/CD44(High) TIL numbers reached peak levels at day 21 that precipitously decreased by day 28 whereas corresponding CD8 cell numbers progressively increased, however, at lower levels and with later kinetics. Intracellular cytokine staining showed that greater numbers of IL-4-producing Th2 cells were elicited and with earlier kinetics than that of IFN-gamma-producing Th1 cells. T cells co-expressing DX5 (CD3(+)/DX5(+)) emerged (>21 days), suggesting a recruitment of NK-like T cells at later stages of tumor progression. Moreover, tumors selectively up-regulated TGF-beta, MIF, and IP-10 gene expression at times as early as day 4, with peak levels at day 7 in vivo. Such gene expression remained elevated and correlated with a continued progression in tumor growth suggesting that preferential effector cell recruitment and production of select factors during different stages of tumor maturation may aid in regulating effective endogenous antitumor responses in progressive breast cancer.
 ...
PMID:Type 1 and type 2 tumor infiltrating effector cell subpopulations in progressive breast cancer. 1509 54

MUC1/sec is a secreted form of the glycoprotein mucin 1 (MUC1). To characterize the role that MUC1 and MUC1/sec have in tumor progression, these genes were expressed in DA-3 mammary tumor cells. DA-3 cells and DA-3 cells expressing the transmembrane MUC1 gene (DA-3/TM) grow with similar kinetics in BALB/c mice. Surprisingly, DA-3 cells expressing and secreting MUC1/sec (DA-3/sec) fail to form tumors in vivo. The mechanism of rejection was evaluated using mice deficient in constituents of the immune system. All mice lacking IFN-gamma, NK, NKT, or macrophages formed DA-3/sec tumors that regressed shortly after implantation. However, progressively growing DA-3/sec tumors developed in mice devoid of T lymphocytes. The importance of T lymphocytes in the rejection of DA-3/sec tumors was further supported by detection of DA-3-specific CTL in mice challenged with the DA-3/sec tumor. Recruitment of appropriate APC and effector cells is an important first step in the tumor clearance. Indeed, DA-3/sec cells or cell supernatants recruited 3-4 times as many macrophages as DA-3/TM cells in vivo, suggesting that a secreted chemotactic product is produced from DA-3/sec cells. RNA and protein analysis of DA-3/sec cells revealed that several genes are up-regulated by MUC1/sec expression, including MCP-1 (CCL-2). These results suggest DA-3/sec cells are capable of recruiting immune cells, and that rejection of DA-3/sec tumors, although aided by cells of the innate immune response, is ultimately due to T cell-mediated events.
 ...
PMID:MUC1/sec-expressing tumors are rejected in vivo by a T cell-dependent mechanism and secrete high levels of CCL2. 1526 1

The differentiation of naive CD4(+) T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity, allergy, and tumor immune surveillance. We previously demonstrated that beta1,6GlcNAc-branched complex-type (N-acetylglucosaminyltransferase V (Mgat5)) N-glycans on TCR are bound to galectins, an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse. Mgat5(-/-) mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis. In this study we examined the role of beta1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation. beta1,6GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle. Anti-CD3-activated splenocytes and naive T cells from Mgat5(-/-) mice produce more IFN-gamma and less IL-4 compared with wild-type cells, the latter resulting in the loss of IL-4-dependent down-regulation of IL-4Ralpha. Swainsonine, an inhibitor of Golgi alpha-mannosidase II, blocked beta1,6GlcNAc N-glycan expression and caused a similar increase in IFN-gamma production by T cells from humans and mice, but no additional enhancement in Mgat5(-/-) T cells. Mgat5 deficiency did not alter IFN-gamma/IL-4 production by polarized Th1 cells, but caused an approximately 10-fold increase in IFN-gamma production by polarized Th2 cells. These data indicate that negative regulation of TCR signaling by beta1,6GlcNAc N-glycans promotes development of Th2 over Th1 responses, enhances polarization of Th2 cells, and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat5(-/-) mice.
 ...
PMID:N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. 1558 41

The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-gamma. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45(+) leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-alpha. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4(+) effector memory T cell. We conclude that quiescent CD4(+) effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-gamma, leading to tumor cell eradication.
 ...
PMID:Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-gamma, and eradicate tumor cells. 1563 12

Neoplastic transformation is a multistep process in which gene products of specific regulatory pathways are involved at each stage. Identification of these overexpressed or mutated gene products provides an unprecedented opportunity to address the immune system against defined antigens and eliminate transformed cells. Mice transgenic for these oncogenes (e.g. HER-2/neu, a prototype of deregulated oncogenic protein kinase membrane receptors) are ideal experimental models for assessing the potential of active immunization. The demonstration that vaccines can cure HER-2/neu transplantable tumors, prevent their onset and delay the progression of preneoplastic lesions in mice at risk suggests that efficient immunological inhibition of HER-2/neu carcinogenesis can be achieved by specific vaccination. To further explore this issue, halting of tumor progression in the mammary glands of BALB-neuT mice with two immunization protocols in two laboratories has been studied independently by DNA microarray analysis. Combination of the two sets of results revealed a clear correlation between them when the tumor mass was titrated by transcription profiling. It was also clear that both protocols induced a strong, polyclonal antibody response and halted tumor growth at a condition very similar to that at which the vaccination began. Differences in the expression profiles were mainly related to the expression levels of a few chemokines and T-cell-specific genes that may be in some way correlated with the efficacy of the vaccination. Last, combination of the expression data with the protection results indicated that chronic vaccination is needed to maintain an active IFN-gamma-mediated response in the mammary gland.
 ...
PMID:Immune prevention of mammary carcinogenesis in HER-2/neu transgenic mice: a microarray scenario. 1569 Feb 7

The predominance of type two cytokines in syngeneic B16 tumor-bearing mice was confirmed by analysing supernatant contents and mRNA copies of IFN-gamma, IL-4, IL-5, IL-10 and IL-13 from splenocytes. The cytokine-producing lymphocytes were then examined by double-staining flowcytometry. Both CD4+IFN-gamma+ T cells and DX5+IFN-gamma+ NK cells from spleen significantly declined, interestingly, the declining degrees of DX5+IFN-gamma+ NK cells were much greater than those of CD4+IFN-gamma+ T cells by the percentage in whole NK or T cells or the absolute amounts per spleen at early tumor stage (day 10) or tumor-advanced stage (day 20). In contrast to DX5+IFN-gamma+ NK cells, DX5+IL-10+ NK cells increased during tumor progression, the increasing degrees of DX5+IL-10+ NK cells were also much greater than those of CD4+IL-10+ T cells by the percentage or the absolute amounts. Though the percentage of DX5+IL-4+ NK cells only increased in early tumor stage (day 10), the increasing degree was also greater than that of CD4+IL-4+ T cells. In 20xfield view under laser confocal microscope, the mean numbers of DX5+IFN-gamma+ NK cells and CD4+IFN-gamma+ T cells dramatically declined after tumor inoculation. These results suggest that cytokines produced by NK cells, at least partly, account for the balance of type one and two cytokines as done by T cells, and in some conditions, that the NK1 or NK2 cells were possibly more sensitive to tumor progression.
 ...
PMID:Tumor-induced suppression of interferon-gamma production and enhancement of interleukin-10 production by natural killer (NK) cells: paralleled to CD4+ T cells. 1582 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>