UMLS:C0684249 - FACTA Search

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early reports suggest that the costimulatory molecule CD86 (B7-2) has sporadic efficacy in tumor immunity, whereas changes in cancer immunity mediated by the MHC class II transactivator (CIITA) have not been extensively investigated. CIITA activates MHC class II expression in most cells; however, in the Line 1 lung carcinoma model system, CIITA activates MHC class I and well as class II. Here we show that CD86 is very effective in inducing a primary immune response against Line 1. Tumor cells expressing CD86 grew in only 50% of the mice injected with live cells, and those mice that developed tumors did so with significantly delayed kinetics. Furthermore, irradiated CD86-expressing Line 1 cells served as an effective tumor vaccine, demonstrating that CD86 is effective in inducing tumor immunity in the Line 1 system. These data suggest that if CIITA and CD86 cooperate, enhanced tumor immunity could be achieved. CIITA alone was mildly beneficial in slowing primary tumor growth but only when expressed at low levels. Clones expressing high levels of class II MHC grew as fast as or faster than parental tumor, and CIITA expression in a tumor vaccine assay lacked efficacy. When CIITA and CD86 were coexpressed, there was no cooperative immune protection from tumor growth. Cells that coexpress both genes also failed as a cancer vaccine, suggesting a negative role for CIITA in this lung carcinoma. These data suggest that human cancer vaccine trials utilizing CIITA gene therapy alone or in combination with CD86 should be approached with caution.
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PMID:Combination gene therapy with CD86 and the MHC class II transactivator in the control of lung tumor growth. 1035 84

A panel of 31 long-term non-small cell lung cancer (NSCLC) cell lines was examined for the expression of protein and/or mRNA transcripts for 11 distinct immune response related molecules or tumor associated antigens (TAA). To assess whether cytokine stimulation might up-regulate expression of the genes of interest, cells were cultured in 500 U/ml of gamma-interferon (gamma-IFN) for 48-72 h prior to analysis. Major histocompatibility complex (MHC) Class I antigens were detected by indirect immunofluorescence and were constitutively expressed on all of the cell lines. The average of the mean fluorescence intensity (MFI) measured 222+/-22. gamma-IFN stimulation produced a significant increase to 482+/-36. For MHC Class II only 7/31 cell lines (23%) exhibited constitutive expression, while gamma-IFN treatment had a dramatic effect and yielded 18/31 (58%) positive cell lines. The co-stimulatory molecules CD80 and CD86 were examined by direct immunofluorescence for cell surface expression and RT-PCR amplification for mRNA. CD80 protein was not detected at all, while an insignificant percentage of cells were positive (mean 2%) for CD86 in all cell lines tested. gamma-IFN had no apparent effect on CD80 or CD86 protein expression. Constitutive CD80 or CD86 mRNA levels were observed in 45 and 61% of the NSCLC lines, respectively. These percentages increased to 77% and 90% with gamma-IFN. Cell surface phenotypic analysis for TAA revealed positive populations in 28/31 cell lines (90%) for Her-2/neu, 18/31 (58%) for CEA and 8/31 (26%) for GD-2, with gamma-IFN having no effect. After gamma-IFN stimulation, RT-PCR amplification for Mage-1, -2, -3 and WT-1 detected mRNA in 33%, 33%, 44% and 70% of the cell lines, respectively. Overall, gamma-IFN stimulation led to the up-regulation of MHC Class I molecules and class II molecules as well as CD80 and CD86 mRNA transcripts. This survey represents the first comprehensive analysis of NSCLC cell lines for a variety of molecules that could play an important role in the generation of an NSCLC anti-tumor CD8+ cytotoxic T lymphocyte (CTL) response.
Lung Cancer
PMID:Characterization of human non-small cell lung cancer (NSCLC) cell lines for expression of MHC, co-stimulatory molecules and tumor-associated antigens. 1155 13

CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-gamma (IFN-gamma) and Mig (monokine induced by IFN-gamma) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.
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PMID:T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines. 1276 90

We examined whether expression of monokine induced by IFN-gamma (Mig, CXCL9) in tumors could produce antitumor effects. Murine lung carcinoma cells (A11) were retrovirally transduced with the murine Mig gene (A11/Mig) and were inoculated into syngeneic mice. Although proliferation in vitro of A11/Mig cells was not different from that of parent cells, the growth in vivo of A11/Mig tumors was significantly retarded compared with that of parent tumors. The antitumor effect was dependent on the amount of Mig produced. We compared the expression level of marker genes of lymphocytes and endothelial cells between parent and A11/Mig tumor masses with reverse transcription-polymerase chain reaction. Expression of CD4, CD8alpha, CD40, CD86, CD28, CD31 and vascular endothelial growth factor was not different between the two tumor groups but expression of CD40 ligand, CD80, NK1.1 and CXCR3 was relatively lower in A11/Mig tumors. Although Mig is a chemotactic factor for activated T and NK cells and an inhibitor for angiogenesis, the present data suggested that production of Mig in tumors did not recruit activated T and NK cells efficiently or suppress angiogenesis. The antitumor effects by Mig could be independent of anti-angiogenesis and recruitment of T and NK cells.
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PMID:Expression of the Mig (CXCL9) gene in murine lung carcinoma cells generated angiogenesis-independent antitumor effects. 1279 44

While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.
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PMID:Dendritic cell-induced activation of adaptive and innate antitumor immunity. 1463 94

Activation of T cells requires co-stimulation, in addition to signals through the antigen-receptor complex. Antigen encounter without adequate co-stimulation results in T-cell desensitization or anergy, a mechanism of peripheral tolerance and an apparent obstacle to cancer immunotherapy. One important co-stimulatory pathway involves CD28 engagement by CD80 or CD86. However, other ligand-receptor pairs can also provide co-stimulation and may have important functions modulating the immune response. Previous reports indicated that co-stimulation using 4-1BB ligand (4-1BBL) or agonistic anti-4-1BB antibodies could prolong T-cell responses, avoid activation-induced cell death and promote anti-tumour responses in mice. To further investigate the potential for cancer immunotherapy, we studied the effects of CD80/CD86 and 4-1BBL in repeated stimulation of human T cells and asked whether 4-1BBL might be capable of reversing anergy. We expressed CD80, CD86 and 4-1BBL in A549 lung carcinoma cells using adenovirus vectors and co-cultured these with human T cells stimulated with anti-CD3 antibody. Proliferation co-stimulated by CD80 or CD86 was transient; however, 4-1BBL-co-stimulated cultures continued to proliferate for up to 5 weeks, with repeated stimulation. Combined co-stimulation with CD80/CD86 and 4-1BBL also allowed continuous proliferation at a faster rate than either signal alone. Co-stimulation with 4-1BBL did not suppress expression of the inducible, inhibitory CD80/CD86R, CTLA-4. Significantly, we show that T cells that had become non-responsive to anti-CD3, either alone or together with CD80/CD86 co-stimulation, and thus were anergic, could be reactivated to proliferate when costimulated with 4-1BBL, either alone or combined with CD80/CD86.
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PMID:Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells. 1797 94

Binding of CD80/86 to CD28 is regarded as the main T cell costimulatory interaction. However, CD28 downregulates soon after T cell activation. To investigate potential cross-interaction between CD137 (4-1BB) and CD28, we stimulated T cells with anti-CD3 in the presence of A549 lung carcinoma cells expressing CD80/CD86 and 4-1BBL molecules, transduced into the cells using recombinant non-replicating adenoviruses. Following initial T cell proliferation, the proportion of CD28(+) cells in both CD4(+) and CD8(+) populations was rapidly reduced by CD80/86 costimulation, whereas cultures costimulated with just 4-1BBL continued to express CD28. CD28 was also downregulated in cultures costimulated with both CD80/86 and 4-1BBL. Interestingly, in cells costimulated with CD80/86 that had downregulated CD28 expression and ceased to proliferate, reactivation of proliferation by 4-1BBL costimulation also restored their CD28 expression. These findings show a positive effect of CD137 signalling on CD28 expression, similar to the effect of CD28 engagement on 4-1BB expression during the initial phases of T cell activation. Moreover, they point to the importance of signals through 4-1BB for the purposes of ex-vivo T cell activation and expansion.
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PMID:4-1BBL costimulation retrieves CD28 expression in activated T cells. 1921 84

Dendritic cells (DCs) have a central role in the development of adaptive immune responses, including antitumor immunity. Factors present in the tumor milieu can alter the maturation of DCs and inhibit their capacity to activate T cells. Using gene expression analysis, we found that human DCs increased the expression of TGF-beta1 transcripts following culture with human lung carcinoma cells (LCCs). These DCs produced increased amounts of TGF-beta1 protein compared with DCs not exposed to tumor cells. LCCs also decreased the expression of CD86 and HLA-DR by immature DCs. Furthermore, LCCs decreased CD86 expression and the production of TNF-alpha and IL-12 p70 by mature DCs. Moreover, LCCs also converted mature DCs into cells producing TGF-beta1. These TGF-beta1-producing DCs were poor at eliciting the activation of naive CD4(+) T cells and sustaining their proliferation and differentiation into Th1 (IFN-gamma(+)) effectors. Instead, TGF-beta1-producing DCs demonstrated an increased ability to generate CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress the proliferation of T lymphocytes. These results identify a novel mechanism by which the function of human DCs is altered by tumor cells and contributes to the evasion of the immune response.
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PMID:Human dendritic cells produce TGF-beta 1 under the influence of lung carcinoma cells and prime the differentiation of CD4+CD25+Foxp3+ regulatory T cells. 1923 74

A dendritic cell (DC) vaccine strategy has been developed as a new cancer immunotherapy, but the goal of complete tumor eradication has not yet been achieved. We have previously shown that baculoviruses potently infect DCs and induce antitumor immunity against hepatomas in a mouse model. Baculovirus-infected, bone marrow-derived DCs (BMDCs) display increased surface expression of costimulatory molecules, such as CD80, CD86 and major histocompatibility complex (MHC) classes I and II, and secrete interferons and other proinflammatory cytokines. In this study, we evaluated the induction of antitumor immunity in mice by baculovirus-infected BMDCs against lung cancer and melanoma. After treatment with baculovirus-infected BMDCs, murine lung tumors caused by Lewis lung carcinoma (LLC) cells were significantly reduced in size, and the survival of the mice was improved. In addition, experiments using a melanoma mouse model showed that baculovirus-infected BMDCs inhibited tumor growth and improved survival compared with controls. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine levels remained normal in baculovirus-infected BMDC-treated mice. Our findings show that baculovirus-infected DCs induce antitumor immunity and pave the way for the use of this technique as an effective tool for DC immunotherapy against malignancies.
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PMID:Induction of antitumor immunity against mouse carcinoma by baculovirus-infected dendritic cells. 2087 26

In our study, we find that photodynamic therapy (PDT), which generates reactive oxygen species (ROS) -mediated endoplasmic reticulum (ER) stress to inflict trauma in the targeted lesion, can break the balance between membrane damage-associated molecular patterns (DAMPs) and integrin-associated protein (CD47). The imbalance undermines the ability of lewis lung carcinoma (LLC) cells to escape immune attack by increasing the uptake of hypericin-mediated PDT(hyp-PDT) killed lewis lung carcinoma (LLC) cells by homologous dendritic cells (DCs), accompanied by phenotypic maturation (CD80^high, CD86^high, and CD40^high) and functional stimulation (NO^high, IL-10^absent) of dendritic cells as well as subsequent T-cell response. Besides, C57BL/6 mice vaccinated with dendritic cells (DCs) pulsed with PDT-treated LLCs (PDT-DCs) or PDT-treated LLCs alone (PDT-LLCs) show potent immunity against LLC tumor. These data identify hypericin-induced PDT as a strong inducer of immunogenic apoptosis, providing an antitumor vaccination strategy for personalized cancer Immunotherapy.
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PMID:Hypericin-based Photodynamic Therapy Induces a Tumor-Specific Immune Response and an Effective DC-based cancer Immunotherapy. 2450 34

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