Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study shows that induction of tumor-specific CD4+ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4+ T cells were of the T helper cell 1 type. The peptide-specific CD4+ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8+ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.
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PMID:Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. 948 Sep 79

Although treatment for hepatocellular carcinoma (HCC) has recently improved, most patients still relapse and die from this disease. The development of new therapeutic and preventive strategies for HCC is, therefore, required. A novel mutant protein (mutein) of human tumor necrosis factor alfa (TNF-alpha mutein F4614, 1SSSRGDSD... 29V ... 155L) was developed to decrease several adverse effects of TNF-alpha. F4614 is known to lack hypotensive effects of human TNF-alpha without losing its anti-tumor effect in mice transplanted with Meth-A sarcoma. Our study investigated the anti-tumor effects of F4614 against hepatoma cells in vitro and in vivo. F4614 significantly inhibited growth of all four tumor cells in vitro. A murine hepatoma cell line, MH134, when incubated in the presence of F4614, exhibited upregulation of surface major histocompatibility complex (MHC) class-I, intercellular adhesion molecule-1 (ICAM-1) and B7-1 molecules, and a decreased proportion of cells in the G2/M phase of the cell cycle. In addition, F4614 induced apoptosis in a significant number of MH134 cells. TNF-alpha and F4614 (5 microg/mouse daily for 5 days) showed similar anti-tumor activities in syngeneic MH134-bearing mice and heterogeneic PLC/PRF/5-bearing athymic nude mice. Intratumoral injection of F4614 or TNF-alpha was more effective than intravenous injection. Immunohistochemical analysis of the tumors treated by F4614 revealed that tumors were surrounded with a large number of Mac-1+ cells and a small number of CD4+ and CD8+ T cells; that suggests that intratumoral injection of F4614 elicited host immunoreactions. Thus, F4614 may be a new strategy for immunotherapy of HCC.
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PMID:A novel human tumor necrosis factor alfa mutein, F4614, inhibits in vitro and in vivo growth of murine and human hepatoma: implication for immunotherapy of human hepatocellular carcinoma. 965 97

Although the central nervous system (CNS) is often regarded as an immunologically privileged site, it is well established that specific CNS immunoreactivity can be generated through peripheral vaccination with CNS antigens. Dendritic cells (DC) are potent antigen presenting cells of hematopoietic origin that have emerged as a promising tool for cancer immunotherapy capable of evoking significant anti-tumor immunity when pulsed with tumor-associated peptides. To explore a role for DC-based immunization strategies for the treatment of CNS tumors, we developed a brain tumor model using the C3 sarcoma cell line which expresses the tumor-specific, major histocompatibility complex (MHC) class I-restricted peptide epitope E7(49-57). Syngeneic C57Bl/6 mice receiving intravenous (i.v.) injections of bone marrow-derived DCs pulsed with E7 peptide were effectively protected against a subsequent intracerebral challenge with C3 tumor cells. More importantly, this systemic immunization strategy was effective in a therapy model as 67% of animals (10 of 15) with established (day 7) intracerebral C3 tumors treated with 3 weekly injections of E7 peptide-pulsed DCs achieved a long-term survival (>90 days) while no control animals survived beyond day 41. In vivo depletion of CD8+ cells, but not CD4+ or asialo-GM1+ cells, abrogated the efficacy of E7 peptide-pulsed DC therapy of established tumors, indicating a pivotal role of specific CD8+ T-cell responses in mediating the anti-tumor effect. Our findings support the hypothesis that effective CNS anti-tumor immunoreactivity can be generated with DC-based tumor vaccines.
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PMID:Bone marrow-derived dendritic cells pulsed with a tumor-specific peptide elicit effective anti-tumor immunity against intracranial neoplasms. 975 52

CD4+ T cells are involved in immune responses against the Meth A sarcoma and infiltrate tumours arising from Meth A cells inoculated intradermally in (BALB/c x C57BL/6)F1 (H-2d/b) mice. In order to investigate whether the prerequisites for tumour antigen presentation to CD4+ T cells are fulfilled within the malignant lesion, expression of class II major histocompatibility complex (MHC) molecules and the costimulatory ligand B7 were examined. The I-Ab and I-Ed allomorphs were abundantly expressed by virtually all B cells and 50% of macrophages infiltrating the tumours. In striking contrast, the I-Ad variant was hardly detectable. This pattern of class II expression appeared to be unique for the tumour microenvironment. Thus the proportion of I-Ad+ spleen B cells and peritoneal macrophages did not significantly differ from the proportion expressing I-Ab and I-Ed, and these extratumoral I-Ad+ cells stained as brightly as did cells from healthy mice. Expression of B7 was weak by tumour-infiltrating cells. The profound capacity of the Meth A sarcoma to confer low local I-Ad and B7 expression might preclude T-cell-dependent anti-tumour immune responses and thus promote survival of malignant cells. Whereas MHC class II genes are generally found to be co-ordinately transcribed, this study demonstrates that the expression of MHC class II allelic variants can be differentially regulated in vivo.
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PMID:Differential expression of major histocompatibility complex class II variants in cells infiltrating the meth A sarcoma. 1032 Jun 43

The significance of CD4+ lymphocytes and major histocompatibility complex (MHC) class II-restricted antigens in antitumor immunity has been demonstrated in several animal models as well as in some human tumors. However, because of the lack of known class II-restricted antigens, the participation of CD4+ cells in antitumor responses has not been well characterized. Recent reports showed that class II proteins covalently linked to an antigenic peptide could be constructed and cells expressing these fusion proteins were recognized by specific TH cells. The aim of this study was to determine the effect of the expression of a class II-peptide construct on the tumorigenicity and immunogenicity of transfected murine tumor cells. We have constructed a gene for I-Ed beta chain covalently coupled to the I-Ed-restricted TH cell determinant of sperm whale myoglobin (SWM132-145). This class II fusion protein was recognized by a specific TH cell line on the surface of COS-7 cells or BALB/c sarcoma cells. The sarcoma cells expressing the MHC-peptide complex were rejected by immunocompetent BALB/c mice, and in vivo T-cell subset depletion experiments suggested the importance of CD4+ cells in the rejection. Moreover, splenocytes from mice immunized with tumor cells expressing the I-Ed-SWM complex showed specific peptide recognition in vitro. Such covalent MHC-peptide complexes could prove useful in studies on the role of CD4+ lymphocytes in antitumor immune responses, and also in designing new, more effective vaccine approaches to the immunotherapy of cancer, as class II-restricted tumor-associated antigens are identified for human cancers.
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PMID:Tumorigenicity and immunogenicity of murine tumor cells expressing an MHC class II molecule with a covalently bound antigenic peptide. 1068 36

A transplantable tumor line (KB) was established in syngeneic rats from a naturally occurring sarcoma that had arisen in the thymus of a 24-month-old male F344 rat. Further, a cell line (KB-P) was induced from KB and a cloned cell line (KB-D8) was isolated from KB-P. The primary thymic tumor and KB tumors showed heterogeneous histological growth patterns such as sheet-like, ill-defined bundle, fascicular and interwoven fashions, consisting of spindle cells, oval cells and histiocytic large round cells. Immunohistochemically, neoplastic cells in KB tumors and KB-P and KB-D8 cultures reacted to vimentin and were labeled with antibodies of OX6 (for rat major histocompatibility complex class-II antigens), ED5 (for rat follicular dendritic cells; FDCs) and RED-1 (for interdigitating dendritic cells) in varying degrees, indicating that neoplastic cells exhibited the immunophenotypes of rat dendritic cells. In addition, neoplastic cells were immunoreactive to ED1 (for rat monocytes/macrophages) and ED2 (for rat tissue macrophages), and also showed positive reactions to histiocytic lysosomal enzymes such as acid phosphatase and non-specific esterase. Ultrastructurally, neoplastic cells had cell surface projections, cisterna-like structures and variously developed lysosomes in the cytoplasm. Based on these findings, the present tumor was regarded as dendritic cell-derived sarcoma capable of expressing macrophage-like and histiocytic nature. A reverse-transcription polymerase chain reaction method revealed that the addition of lipopolysaccharide dose dependently increased the expression of mRNA of transforming growth factor-beta1, a proinflammatory factor, in KB-D8 cells. The transplantable line (KB) and cell lines (KB-P and KB-D8) may become useful tools for studying the histogenesis and pathobiological functions of dendritic cells.
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PMID:Establishment and characterization of transplantable tumor line (KB) and cell lines (KB-P and KB-D8) from a rat thymus-derived dendritic cell sarcoma. 1207 Jun 2

The development of an effective antitumor immune response to control tumor growth is influenced by the tumor cell itself and/or by the tumor microenvironment. Tumor invasion and tumor cell spreading require a finely tuned regulation of the formation and loosening of adhesive contacts of tumor cells with the extracellular matrix (ECM). In our laboratory, a rat tumor cell line derived from a spontaneous rat sarcoma revealed, by flow cytometry, a high frequency of intercellular adhesion molecule-1 (ICAM-1, 70.1 +/- 8.7%) and urokinase-type plaminogen activator receptor (uPAR, 51.2 +/- 5.2%) positive cells, while a weak expression of MHC class II (IA, 2.2 +/- 0.2% and IE, 17.4 +/- 3.7%) and B7 (12.1 +/- 2.2%) antigens was detected. In our tumor experimental model, after implantation of tumor cells, visible tumor masses were present at days 5-7 with a relatively fast tumor growth until day 15 (progressive phase) followed by a suppression of the tumor growth (regressive phase). Here we present data that correlates a significant decrease in the frequency of ICAM-1 and uPAR expressing tumor cells with the appearance of tumor cells in sites distant from that of the primary tumor. In addition we describe the development of a cellular immune response which controls the tumor progression and is associated with an increase in the expression of major histocompatibility complex (MHC) class II IA antigen during tumor development. The histological examination at tumor progressive and regressive time points revealed the relevant presence of polymorphonuclear neutrophils (PMNs) evidencing colliquative necrosis in tumor growth areas. Taken together, these results support the idea that the balance between adhesive interactions, proteolytic activity and tumorigenicity may lead to a tumor invasive phenotype.
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PMID:Decreased expression of intercellular adhesion molecule-1 (ICAM-1) and urokinase-type plasminogen activator receptor (uPAR) is associated with tumor cell spreading in vivo. 1219 72

Basically, dendritic cell-derived sarcomas are characterized by expression of major histocompatibility complex class-II molecules, but the biological properties of the tumor cells remain to be elucidated. Recently, we established a novel transplantable cell line (KB-D8) from a dendritic cell sarcoma found in an F344 rat. In the present study, we investigated immunophenotypical changes of KB-D8 tumor cells and tumor-associated macrophages (TAMs) appearing in relation to tumor development in syngeneic F344 rats. A number of neoplastic cells in 0.5-cm-diameter KB-D8 tumors showed immunoreactions to OX6 (specific for rat antigen-presenting cells), ED1 (for rat exudate macrophages), and ED2 (for rat resident macrophages), and 72% and 11% of the OX6+ cells were double-immunostained with ED1 and ED2, respectively. Interestingly, the immunoreactions to these antibodies were gradually reduced with increasing size of KB-D8 tumors of 1-, 2-, and 3-cm diameter. These findings indicated that immunophenotypes of dendritic cell-derived sarcomas may be changeable depending on microenvironmental conditions in vivo. Many TAMs seen outside KB-D8 tumors reacted to OX6, ED1, and ED2; the numbers of TAMs immunopositive for these antibodies also decreased as the tumor grew. Similarly, the earlier temporary increase and subsequent gradual decrease in ED2+ and OX6+ cell numbers were observed in the spleen and liver of KB-D8-bearing rats. The reverse-transcription polymerase chain reaction showed mRNA expressions of granulocyte/macrophage-colony stimulating factor, monocyte-chemoattractant protein-1, and osteopontin in KB-D8 tumor tissues. Although the functional roles (biphasic roles: suppressing or promoting) of these factors should be investigated further in relation to tumor development, the factors might be partially responsible for the TAM reactions. KB-D8 would be a useful experimental model to investigate the biological characteristics of dendritic cell sarcomas and tumor immunology in the host.
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PMID:Immunophenotypical changes of neoplastic cells and tumor-associated macrophages in a rat dendritic cell sarcoma-derived transplantable tumor line (KB-D8). 1259 65

In addition to their role in antigen presentation, major histocompatibility complex (MHC) class II molecules have been widely described as signaling proteins in diverse antigen-presenting cells (APCs) including B cells and dendritic cells. By contrast, little is known of the signaling function of MHC class II molecules expressed in solid tumors. We describe the functional organization and signaling ability of I-Ak expressed in a sarcoma, and report the recruitment of I-Ak to lipid rafts after MHC class II engagement. Lipid raft integrity was required for I-Ak-mediated reorganization of the actin cytoskeleton and translocation of protein kinase C-alpha(PKC-alpha) to the precise site of stimulation via I-Ak. Truncation of the intracytoplasmic domains of I-Ak did not perturb I-Ak recruitment to lipid rafts but abrogated PKC-alpha translocation and actin rearrangement. PKC-alpha was detected in lipid microdomains and enrichment of activated PKC-alphain lipid rafts was induced by I-Ak signaling. Ordering of the molecular events following engagement of the MHC class II molecules revealed that I-Ak recruitment to lipid rafts precedes signaling. This is consistent with the absence of a requirement for the intracytoplasmic tails for localization to lipid rafts. These data reveal that lipid-rich microdomains play a key role in MHC class II-mediated signaling in a solid tumor.
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PMID:Intracytoplasmic domains of MHC class II molecules are essential for lipid-raft-dependent signaling. 1276 88

Tumor cells cannot activate T lymphocytes, since they do not usually express major histocompatibility complex (MHC) class II molecules. Thus, tumor antigens can only be presented indirectly to T cells through professional antigen-presenting cells (APC). In our laboratory, we have treated a tumor cell line (Tu1-A) - derived from an induced rat mammary sarcoma - in order to increase the expression of MHC class I and class II molecules. In our tumor model, the transference of these induced cells into normal rats generated a tumor mass that exhibited a lower tumor growth rate and an earlier regression as compared to those observed in rats inoculated with wild-type Tu1-A cells. This earlier tumor regression was associated with the development of an antigen-specific immune response. 85-87% of the rats in both groups rejected the tumor and were alive at day 60 after tumor cell inoculation. However, in rats treated with wild-type cells the rejection was delayed and took place after tumor ulceration. Rats that had rejected tumors were rechallenged with wild-type cells in order to assay the presence of a long-lived antitumor immunity. All the animals were resistant to the second tumor challenge. We conclude that the development of a specific immune response could be achieved by the superexpression of MHC molecules on tumor cells or when tumor ulceration promotes APC to take up necrotic cells and tumor antigens are presented to T lymphocytes.
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PMID:Immune control of tumors by antigen presentation improvement. 1500 35


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