Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major goal of this study was to examine the effects of total-body irradiation (TBI) on lung carcinoma progression and determine if changes in tumor growth could be correlated with radiation-induced alterations of immune system parameters. Lewis lung tumor cells were injected subcutaneously into syngeneic C57BL/6 mice that had been irradiated with a single 3.0 Gy dose of gamma-rays (60Co) at four time points either before or after tumor cell implantation. Subsequently, a second group of mice was irradiated 2 h prior to tumor injection with sequential doses of gamma-rays (0.46-2.66 Gy range). Assays were performed on blood and spleen from mice euthanized 16 days postimplantation. Tumor growth was consistently slower regardless of the timing of radiation exposure. However, dose of radiation influenced tumor growth delay. The preirradiated tumor-bearing mice had high CD4/CD8 T lymphocyte ratios along with increasing percentages of NKT cells in the blood supply with dose. Tumor-induced immunomodulation was also present, as evidenced by splenomegaly, low proliferative response to mitogens, and decreased spontaneous blastogenesis of leukocytes within the blood compared with normal values (P < or = 0.01). Anemia and thrombocytopenia were not observed with either tumor presence or irradiation. The present study demonstrates that a modest dose of TBI prior to tumor cell implantation resulted in a beneficial antitumor effect. A selective radiation-induced depletion of CD8+ T lymphocytes and changes in NKT cell percentages, correlated with findings from cytotoxicity assays, were indicative of a protumoricidal immune environment.
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PMID:Dose and timing of total-body irradiation mediate tumor progression and immunomodulation. 1220 76

We have isolated several cytotoxic T lymphocyte (CTL) clones from lymphocytes infiltrating a lung carcinoma of a patient with long survival. These clones showed a CD3+, CD8+, CD4-, CD28- phenotype and expressed a T-cell receptor (TCR) encoded either by Vbeta8-Jbeta1.5 or Vbeta22-Jbeta1.4 rearrangements. Functional studies indicated that these clones mediated a high human leukocyte antigen (HLA)-A2.1-restricted cytotoxic activity against the autologous tumor cell line. Interestingly, TCRbeta chain gene usage indicated that CTL clones identified in vitro were selectively expanded in vivo at the tumor site as compared to autologous peripheral blood lymphocytes (PBL). These findings provide evidence that an immune response may take place in non-small cell lung carcinoma and that effector T cells may contribute to tumor regression. Further study indicated that the CTL clones recognized the same decamer peptide encoded by a mutated alpha-actinin-4 gene. Using tetramers of soluble HLA-A2 molecules loaded with the mutated antigenic peptide, we have derived several anti-alpha-actinin-4 T-cell clones from patient PBL. These CTL, recognizing a truly tumor-specific antigen, may play a role in the clinical evolution of this lung cancer patient. Adoptive transfer of CTL clones in a SCID/NOD mice model transplanted with autologous tumor supported their antitumor effect in vivo.
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PMID:Antitumor cytotoxic T-lymphocyte response in human lung carcinoma: identification of a tumor-associated antigen. 1244 85

Fractalkine (FK, also called neurotactin or CX3CL1) is a CX3C chemokine that can chemoattract T lymphocytes, monocytes and NK cells. In our study, we investigated the induction of antitumor response by FK gene transfer. FK gene-modified 3LL lung carcinoma cells (3LL-FK) could both secrete soluble form and express membrane-bound form of FK. The tumor growth of 3LL-FK was decreased. Vaccination with 3LL-FK was effective in the induction of protective immunity and CTL. In vivo depletion analysis demonstrated that CD8(+) T cells are the main participating cells of the antitumor response. Obvious infiltrations of CD8(+) T cells, CD4(+) T cells and dendritic cells (DC) were observed in the tumor sites, suggesting that 3LL-FK might induce antitumor immunity through chemoattraction and activation of T cells and DC. Then we investigated the chemoattraction and activation of DC by 3LL-FK. Chemotaxis assay showed that the supernatants of 3LL-FK could chemoattract immature DC, which were found to express FK receptor CX3CR1, and the immature DC could obviously adhere to 3LL-FK. Adherence of DC to 3LL-FK resulted in phenotypic maturation and upregulated IL-12 secretion of DC, and more strong stimulation of allogeneic T-cell proliferation by DC. The increased production of IL-2 and IFNgamma in 3LL-FK tumor tissue was also observed. Our data suggested that FK gene transfer to tumor cells could induce T-cell-dependent antitumor immunity through chemoattraction and activation of DC.
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PMID:Fractalkine transgene induces T-cell-dependent antitumor immunity through chemoattraction and activation of dendritic cells. 1245 35

In order to study the vaccine potency of gene-modified tumor cells, IL-12 express vector was constructed by using retrovirus. The vector was transfected into EL-4 thymic lymphoma cells and the effect of transfectant on anti-tumor immunity was investigated. The tumorigenicity of EL-4/IL-12 transfectant in syngeneic C57BL/6 mice was decreased significantly after implanted with EL-4/IL-12 transfectant compared with EL-4/Wt or EL-4/Neo groups (P < 0.001). The systemic protective immunity was induced against the challenge with EL-4/Wt (in 8/10 mice) after the rejection of EL-4/IL-12 in vivo experiment, a stronger CTL activity against EL-4/Wt cells and a weak killer activity against syngeneic Lewis lung carcinoma (LLC) cells were obtained in (51)Cr release assay. In vivo depletion analysis suggested that the decreased tumorigenicity mainly depended on CD4(+), CD8(+) and NK cells. Therapeutic vaccines with EL-4/IL-12 cells could retard the growth of established EL-4/Wt tumors significantly compared with those of EL-4/Neo (P < 0.005). These studies suggested that immunotherapy and gene therapy using IL-12 is effective in hematopoietic malignancy and IL-12 has prospects of application in human cancer treatment in the near future.
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PMID:[Effect of Tumor Vaccine of EL-4 Cell Transduced with IL-12 Gene in C57BL/6 Mice] 1257

Prostaglandin E(2) (PGE(2)), a major COX metabolite, plays important roles in several facets of tumor biology. We characterized the contribution of the PGE(2) EP2 receptor to cancer-associated immune deficiency using EP2(-/-) mice. EP2(-/-) mice exhibited significantly attenuated tumor growth and longer survival times when challenged with MC26 or Lewis lung carcinoma cell lines as compared with their wild-type littermates. While no differences in T cell function were observed, PGE(2) suppressed differentiation of DCs from wild-type bone marrow progenitors, whereas EP2-null cells were refractory to this effect. Stimulation of cells in mixed lymphocyte reactions by wild-type DCs was suppressed by treatment with PGE(2), while EP2(-/-)-derived DCs were resistant to this effect. In vivo, DCs, CD4(+), and CD8(+) T cells were significantly more abundant in draining lymph nodes of tumor-bearing EP2(-/-) mice than in tumor-bearing wild-type mice, and a significant antitumor cytotoxic T lymphocyte response could be observed only in the EP2(-/-) animals. Our data demonstrate an important role for the EP2 receptor in PGE(2)-induced inhibition of DC differentiation and function and the diminished antitumor cellular immune responses in vivo.
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PMID:Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. 1261 27

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

Autoantibodies have defined two paraneoplastic visual disorders related to small-cell lung carcinoma: retinopathy ("CAR"-IgG [23kDa, recoverin]) and optic neuritis collapsin response-mediated protein 5 (CRMP-5-IgG [62kDa]). Among 16 patients with CRMP-5-IgG and optic neuritis (aged 52-74 years; all smokers, 9 women), we documented coexisting retinitis in 5. None had CAR-IgG. Fifteen had subacute vision loss, swollen optic discs, and field defects. Vascular leakage was evident at and remote from the disc; 5/5 tested had abnormal electroretinograms. Nine had striking vitreous cells. Vitrectomy showed reactive lymphocytosis (4/4), predominantly CD4(+) (1/1). Most patients had multifocal neurological accompaniments. Cerebrospinal fluid contained lymphocytes (7-32), elevated protein, multiple oligoclonal immunoglobulin bands, and CRMP-5-IgG. Three patients superficially resembled Devic's disease at presentation. One autopsied patient had predominantly CD8(+) T lymphocytes infiltrating optic nerve and spinal cord. Eleven patients had confirmed small-cell carcinoma; 1 had imaging evidence of lung cancer; 3 had renal or thyroid carcinoma. Full-length CRMP-5 protein was identified in normal retina and optic nerve by Western blot analyses. Photoreceptor cells, retinal ganglion cells, and nerve fibers exhibited CRMP-5-specific immunoreactivity. In summary, CRMP-5-IgG defines a paraneoplastic ophthalmological entity of combined optic neuritis and retinitis with vitreous inflammatory cells. Positive serology obviates the need for vitreous biopsy and expedites the search for cancer.
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PMID:Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. 1283 19

Interferon-gamma (IFN-gamma) has been used in the experimental treatment of cancer with limited success. Despite direct cytotoxic effects on tumor cells and the ability to stimulate the antitumor activities of a variety of effector cells, IFN-gamma has not been found to produce impressive therapeutic responses partly because of inadequate sustained intratumoral concentrations and systemic toxicity. To overcome these obstacles, we have developed an antibody/murine IFN-gamma fusion protein (chTNT-3/muIFN-gamma), which utilizes the tumor necrosis therapy antibody, chTNT-3, to target murine IFN-gamma to necrotic regions of solid tumors implanted in immunocompetent BALB/c mice. The genetically engineered fusion protein was expressed in NS0 cells using the Glutamine Synthetase Gene Amplification Expression System. After purification, the fusion protein demonstrated both antigen targeting and cytokine activities as assessed by in vitro assays which, when compared to recombinant free IFN-gamma, demonstrated approximately 40-45% biologic activity by two separate assay determinations. Pharmacokinetic and biodistribution studies in mice demonstrated a relatively long whole body half-life of 32 h in vivo and significant intratumoral accretion, respectively. Most importantly, immunotherapeutic studies in the MAD109 syngeneic murine carcinoma of the lung demonstrated significant intratumoral infiltration by leukocytes, primarily by macrophages and CD4(-) CD8(-) Thy-1.2(+) lymphocytes. Additionally, intravenous administration of the fusion protein significantly decreased the number of metastatic foci in an experimental model of pulmonary metastasis without causing any observable toxicity. These studies demonstrate that chTNT3/muIFN-gamma can safely target syngeneic tumor models as part of a promising strategy for the targeted immunotherapy of solid tumors.
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PMID:Chimeric TNT-3 antibody/murine interferon-gamma fusion protein for the immunotherapy of solid malignancies. 1451 65

We have generated mice null for IFN-beta and report the diverse consequences of IFN-beta for both the innate and adaptive arms of immunity. Despite no abnormalities in the proportional balance of CD4 and CD8 T cell populations in the peripheral blood, thymus, and spleen of IFN-beta-/- mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor alpha production, relative to IFN-beta+/+ mice. Notably, constitutive and induced expression of tumor necrosis factor alpha is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN-beta-/- mice. We also observe an altered splenic architecture in IFN-beta-/- mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN-beta-/- mice, associated with a decrease in B220+ve/high/CD43-ve BM-derived cells and a reduction in BP-1, IgM, and CD23 expression. Circulating IgM-, Mac-1-, and Gr-1-positive cells are also substantially decreased in IFN-beta-/- mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by the reduction of colony-forming units, granulocyte-macrophage. We proceeded to evaluate the in vivo growth of malignant cells in the IFN-beta-/- background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN-beta-/- mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-beta is required during different stages of maturation in the development of the immune system.
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PMID:Critical roles for IFN-beta in lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha. 1459 17

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


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