Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We are evaluating the immune enhancing activities of cytokines for their optimum utility in augmenting cellular immune responses against lung cancer. In this study, we evaluated the mechanism of antitumor responses following IL-7 administration to mice bearing established Lewis lung cancer. IL-7 decreased tumor burden with concomitant increases in the frequency of CD4 and CD8 T lymphocyte subsets, T cell activation markers CXCR3, CD69, and CD127(low), effector memory T cells, and T cell cytolytic activity against parental tumor cells. Accompanying the antitumor responses were increases in IFN-gamma, CXCL9, CXCL10, and IL-12. Individual neutralization of CD4, CD8 T lymphocytes, or the CXCR3 ligands CXCL9 and CXCL10 reversed the antitumor benefit of IL-7, indicating their importance for optimal responses in vivo. Furthermore, IL-7 decreased the tumor-induced apoptosis of T cells with subsequent decrease of the proapoptotic marker Bim. We assessed the impact of IL-7 treatment on regulatory T cells that negatively impact antitumor immune responses. IL-7 decreased regulatory T Foxp3 as well as cell suppressive activity with a reciprocal increase in SMAD7. These results indicate that IL-7 induces CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.
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PMID:IL-7 promotes CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer. 1945 92

An 82-year-old man received right upper lobectomy for lung cancer in April 2006. In August, 2006, he was readmitted to our hospital due to left cervical and left inguinal lymph node swelling. A pathologic diagnosis of diffuse large B-cell lymphoma (DLBCL) was made from a biopsy specimen of the left cervical lymph node. The immunophenotype of the lymphoma cells was CD2-, sCD3-, cCD3-, CD4+, CD5+, CD7-, CD8-, CD10-, CD19+, CD20+, CD23+, CD25+, kappa+, lambda-, CD56-, and dual staining confirmed that the cells were positive for both CD4 and CD19. From these findings, he was diagnosed with CD4-positive DLBCL. Five cycles of R-CHOP were performed and complete remission was achieved. To our knowledge, this is the first report of CD4-positive DLBCL.
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PMID:[CD4-positive diffuse large B-cell lymphoma]. 1963 25

We show correlation between strong and decreased NY-ESO-1-specific immunity with spontaneous regression and subsequent recurrence, respectively, in a long-surviving patient with an NY-ESO-1-expressing lung adenocarcinoma. An integrated immune response consisting of IgG antibody, as well as CD4 and CD8 T cells, against NY-ESO-1 was observed at the time of spontaneous regression of multiple pleural metastases. After tumor dormancy for 3 years, the tumor started to progress. IgG antibody levels and the number of CD4 and CD8 T cells against NY-ESO-1 decreased, but were still detectable. On the other hand, the number of Foxp3+ CD25 high T regulatory cells gradually increased. The findings suggest the relevance of the NY-ESO-1 immune response and its regulation by Foxp3+ CD25 high T regulatory cells in the clinical course of this lung cancer patient.
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PMID:Correlation of high and decreased NY-ESO-1 immunity to spontaneous regression and subsequent recurrence in a lung cancer patient. 1979 34

The current study characterized peripheral blood mononuclear cells (PBMC) obtained from leukapheresis products of patients with non-small cell lung cancer (NSCLC) for cytokine release, the ability to incorporate tritiated thymidine following stimulation using PHA as well as the levels of both CD4 and CD8 regulatory T cells (Tregs) as defined by FoxP3 expression. Results were compared to normal donor PBMC obtained from buffy coat products. Heterogeneous levels of Th1 (gamma interferon and IL-2), Th2 (IL-10 and IL-13), pro-inflammatory (TNF-alpha and IL-6) and the hematopoietic inducing cytokine GMCSF were detected from both populations of PBMC as measured using ELISA. Overall, we observed that combined levels of Th1 and Th2 cytokines were higher in lung cancer patients compared to that seen in normal donor PBMC. The increased cytokine production was coupled with an observed decrease in the ability of lung cancer patient PBMC to incorporate tritiated thymidine. Furthermore, cytokine containing supernatants obtained from patients inhibited the incorporation of tritiated thymidine from PBMC obtained from normal donors. Thus, the combined cytokines which included high levels of IL-10, appeared to exhibit suppressive functional activity. While not statistically significant, the overall trend toward a Th2 cytokine environment was supported by an increased level of Tregs observed in the leukapheresis products of lung cancer patients. These levels were variable and were accompanied by higher than normal levels of CD8+ cells co-expressing FoxP3. Finally, tumor biopsies were examined from lung cancer patients along with autologous normal adjacent tissue (NAT). In these studies, both gamma interferon and IL-10 were detected. The levels of IL-10 in the LPS stimulated cultures were statistically greater from the cancer biopsies compared to the NAT. The current study confirms many earlier results in a comprehensive manner and extends the analysis to leukapheresis products. An environment is described in cancer patients which is characterized by increased cytokine production and decreased proliferative potential likely under the influence of a significant population of regulatory T cells (Tregs). Taken together, these results are discussed as they relate to the potential implications in lung cancer patients immune response to their disease.
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PMID:Characteristics of PBMC obtained from leukapheresis products and tumor biopsies of patients with non-small cell lung cancer. 1988

The dual role of tumour-infiltrating macrophages and lymphocytes on nonsmall cell lung cancer (NSCLC) progression and prognosis may be due to the differential activity of their phenotypes. To investigate the impact of inflammatory cells on NSCLC, we first quantified the number of macrophages (CD68+) and lymphocytes (CD8+ and CD4+) and the percentage of CD8+ cells expressing IL-10 (CD8+/IL-10+) in tumour stroma and epithelium. Then, we evaluated the possible relationships between the numbers of these cells and the clinicopathological features and the overall survival of patients. Paraffin-embedded sections of surgical specimens from 64 patients who had undergone surgery for NSCLC were immunostained with antibodies directed against CD68, CD4, CD8 and IL-10. The percentage of CD8+/IL-10+ cells was higher in cancer stroma of patients with stage I NSCLC than in those with stages II, III, and IV. High percentages of stromal CD8+/IL-10+ cells were associated with longer overall patient survival. In contrast, the number of CD68+, CD8+ and CD4+ cells did not differ between stage I NSCLC and stages II, III, and IV. In conclusion, the survival advantage of patients with stage I NSCLC may be related to the anti-tumour activity of the CD8+/IL-10+ cell phenotype.
Lung Cancer 2010 Sep
PMID:CD8+ T cells expressing IL-10 are associated with a favourable prognosis in lung cancer. 2008 29

Boosting pre-existing, naturally occurring cytolytic CD8(+) T-cell (CTLs) responses directed against class-I MHC-restricted peptides of tumor antigens, represents a primary goal of cancer immunotherapy. The number of pre-existing antitumor CTLs and their impaired function has been incriminated as the most likely candidates for the reduced clinical efficacy of these trials. This study was scheduled to determine possible differences in the frequency and the function of naturally occurring CTL precursors (pCTLs) against multiple peptides derived from the cancer-testis antigens MAGE-A1 and MAGE-A3, and the overexpressed antigen hTERT, in newly diagnosed lung cancer patients as compared with aged-matched healthy individuals. The cumulative frequency of circulating peptide-specific pCTLs was found significantly higher in the cancer patients, varied widely and was not affected by radiotherapy and chemotherapy. Furthermore, this frequency was greatly different between the various tumor-antigen peptides. Under the light of recent evidence provided from animal models, these results indicate that the peptide-specific pCTL frequency might represent an important determinant for the fate of cancer immunotherapy. In addition, our results show that tumor-specific pCTLs of cancer patients can present functional differences regarding their proliferative capacity, intensity of multimer staining and lytic capacity, when compared with those of healthy individuals. Hence, our findings could have an important role for the design of improved immunotherapeutic approaches for lung cancer.
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PMID:Naturally occurring tumor-specific CD8+ T-cell precursors in individuals with and without cancer. 2014 37

The role of chemokines in the pathogenesis of lung cancer has been increasingly appreciated. Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) is secreted from tumor cells and associated tumor stromal cells. The blockade of CCL2, as mediated by neutralizing antibodies, was shown to reduce tumorigenesis in several solid tumors, but the role of CCL2 in lung cancer remains controversial, with evidence of both protumorigenic and antitumorigenic effects. We evaluated the effects and mechanisms of CCL2 blockade in several animal models of non-small-cell lung cancer (NSCLC). Anti-murine-CCL2 monoclonal antibodies were administered in syngeneic flank and orthotopic models of NSCLC. CCL2 blockade significantly slowed the growth of primary tumors in all models studied, and inhibited lung metastases in a model of spontaneous lung metastases of NSCLC. In contrast to expectations, no significant effect of treatment was evident in the number of tumor-associated macrophages recruited into the tumor after CCL2 blockade. However, a change occurred in the polarization of tumor-associated macrophages to a more antitumor phenotype after CCL2 blockade. This was associated with the activation of cytotoxic CD8(+) T lymphocytes (CTLs). The antitumor effects of CCL2 blockade were completely lost in CB-17 severe combined immunodeficient mice or after CD8 T-cell depletion. Our data from NSCLC models show that CCL2 blockade can inhibit the tumor growth of primary and metastatic disease. The mechanisms of CCL2 blockade include an alteration of the tumor macrophage phenotype and the activation of CTLs. Our work supports further evaluation of CCL2 blockade in thoracic malignancies.
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PMID:Monocyte chemoattractant protein-1 blockade inhibits lung cancer tumor growth by altering macrophage phenotype and activating CD8+ cells. 2039 32

Lung CD8(+) T cells might contribute to progression of chronic obstructive pulmonary disease (COPD) indirectly via IFN-gamma production or directly via cytolysis, but evidence for either mechanism is largely circumstantial. To gain insights into these potential mechanisms, we analyzed clinically indicated lung resections from three human cohorts, correlating findings with spirometrically defined disease severity. Expression by lung CD8(+) T cells of IL-18R and CD69 correlated with severity, as did mRNA transcripts for perforin and granzyme B, but not Fas ligand. These correlations persisted after correction for age, smoking history, presence of lung cancer, recent respiratory infection, or inhaled corticosteroid use. Analysis of transcripts for killer cell lectin-like receptor G1, IL-7R, and CD57 implied that lung CD8(+) T cells in COPD do not belong to the terminally differentiated effector populations associated with chronic infections or extreme age. In vitro stimulation of lung CD8(+) T cells with IL-18 plus IL-12 markedly increased production of IFN-gamma and TNF-alpha, whereas IL-15 stimulation induced increased intracellular perforin expression. Both IL-15 and IL-18 protein expression could be measured in whole lung tissue homogenates, but neither correlated in concentration with spirometric severity. Although lung CD8(+) T cell expression of mRNA for both T-box transcription factor expressed in T cells and GATA-binding protein 3 (but not retinoic acid receptor-related orphan receptor gamma or alpha) increased with spirometric severity, stimulation of lung CD8(+) T cells via CD3epsilon-induced secretion of IFN-gamma, TNF-alpha, and GM-CSF, but not IL-5, IL-13, and IL-17A. These findings suggest that the production of proinflammatory cytokines and cytotoxic molecules by lung-resident CD8(+) T cells contributes to COPD pathogenesis.
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PMID:Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15. 2042 67

Nonsmall cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths in the United States. We are developing cell-based vaccines as a new approach for the treatment of NSCLC. NSCLC is broadly divided into 3 histologic subtypes: adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Since these subtypes are derived from the same progenitor cells, we hypothesized that they share common tumor antigens, and vaccines that induce immune reactivity against 1 subtype may also induce immunity against other subtypes. Our vaccine strategy has focused on activating tumor-specific CD4(+) T cells, a population of lymphocytes that facilitates the optimal activation of effector and memory cytotoxic CD8(+) T cells. We now report that our NSCLC MHC II vaccines prepared from adeno, squamous or large cell carcinomas each activate CD4(+) T cells that cross-react with the other NSCLC subtypes and do not react with HLA-DR-matched normal lung fibroblasts or other HLA-DR-matched nonlung tumor cells. Using MHC II NSCLC vaccines expressing the DR1, DR4, DR7 or DR15 alleles, we also demonstrate that antigens shared among the different subtypes are presented by multiple HLA-DR alleles. Therefore, MHC II NSCLC vaccines expressing a single HLA-DR allele activate NSCLC-specific CD4(+) T cells that react with the 3 major classes of NSCLC, and the antigens recognized by the activated T cells are presented by several common HLA-DR alleles, suggesting that the MHC II NSCLC vaccines are potential immunotherapeutics for a range of NSCLC patients.
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PMID:MHC II lung cancer vaccines prime and boost tumor-specific CD4+ T cells that cross-react with multiple histologic subtypes of nonsmall cell lung cancer cells. 2047 49

Several chemokines are used for immunotherapy against cancers because they can attract immune cells such as dendritic and cytotoxic T cells to augment immune responses. Radiofrequency ablation (RFA) is used to locally eliminate cancers such as hepatocellular carcinoma (HCC), renal cell carcinoma, and lung cancer. Because HCC often recurs even after an eradicative treatment with RFA, additional immunotherapy is necessary. We treated tumor-bearing mice by administering ECI301, an active variant of CC chemokine ligand 3, after RFA. Mice were injected s.c. with BNL 1ME A.7R.1, a murine hepatoma cell line, in the bilateral flank. After the tumor became palpable, RFA was done on the tumor of one flank with or without ECI301. RFA alone eliminated the treated ipsilateral tumors and retarded the growth of contralateral non-RFA-treated tumors accompanied by massive T-cell infiltration. Injection of ECI301 augmented RFA-induced antitumor effect against non-RFA-treated tumors when administered to wild-type or CCR5-deficient but not CCR1-deficient mice. ECI301 also increased CCR1-expressing CD11c(+) cells in peripheral blood and RFA-treated tumors after RFA. Deficiency of CCR1 impairs accumulation of CD11c(+), CD4(+), and CD8(+) cells in RFA-treated tumors. Furthermore, in IFN-gamma-enzyme-linked immunospot assay, ECI301 augmented tumor-specific responses after RFA whereas deficiency of CCR1 abolished this augmentation. Thus, we proved that ECI301 further augments RFA-induced antitumor immune responses in a CCR1-dependent manner.
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PMID:Antitumor effect after radiofrequency ablation of murine hepatoma is augmented by an active variant of CC Chemokine ligand 3/macrophage inflammatory protein-1alpha. 2066 2


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