Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell activation involves multiple signaling pathways. In this report, we conducted in vitro and in vivo immune function analysis of tumor-draining lymph node (TDLN) cells after anti-CD3/anti-CD28 activation versus anti-CD3 activation alone in a murine tumor model. In cytokine release assays, the doubly activated TDLN cells secreted significantly greater amounts of IFN-gamma and GM-CSF in response to specific tumor antigen compared with anti-CD3 activated cells. In adoptive immunotherapy, the doubly activated TDLN cells were more effective in mediating regression of 3-day pulmonary metastases compared with anti-CD3 activated cells. Although there was predominant proliferation of CD8+ cells after either activation procedure, the mean-fold expansion of CD4+ cells was significantly greater after anti-CD3/anti-CD28 activation than anti-CD3 activation alone. Using magnetic bead-enriched T-cell subsets, we found that either CD4+ or CD8+ doubly activated TDLN cells could independently mediate tumor regression. Furthermore, the doubly activated CD4+ cells were more effective than CD8+ cells in adoptive immunotherapy on a per-cell basis. The antitumor activity mediated by CD4+ or CD8+ cells could be significantly enhanced with the exogenous administration of IL-2. CD28 co-stimulation of tumor-primed lymphoid cells promotes the generation of potent tumor reactive effector cells, particularly CD4+ T cells, with antitumor activity in adoptive immunotherapy.
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PMID:Therapeutic effects of tumor reactive CD4+ cells generated from tumor-primed lymph nodes using anti-CD3/anti-CD28 monoclonal antibodies. 1214 53

Immunotherapy and combination treatments such as biochemotherapy have shown promise, with higher response rates and a subset of durable responses; however, as the majority of responses are still of short duration, they do not provide any survival benefit. There is therefore a great need to better understand the mechanisms whereby tumours escape immune surveillance. The present study examines the expression of CD28 in patients with untreated and treated melanoma metastases. Twenty-eight patients with metastatic malignant melanoma were treated by biochemotherapy (cisplatinum 30 mg/m(2) days 1-3, DTIC 250 mg/m(2) days 1-3 i.v., and IFN-alpha2b 10 million IU s.c. three days a week for 28 days treatment cycle). Tumours were resected post-biochemotherapy and analysed for the expression of CD28 in CD4(+) and CD8(+) lymphocytes in areas where histopathological regressive changes had occurred, and close to tumour cells in areas of unaffected tumour growth using a double-staining technique. A high percentage of the lymphocytes in areas with regressive changes were found to be CD4(+)CD28(-). In contrast, the vast majority of CD4(+) lymphocytes migrating close to the tumour cells were found to be CD28(+) (P<0.001). A similar difference in the expression of CD28 was also found for the CD8(+) subset (P=0.004). A difference in down-regulation of the expression of CD28 was found between CD4(+) and CD8(+) lymphocytes both in the areas of regressive changes and in the unaffected tumour areas. The present study demonstrates that extensive down-regulation of the co-stimulatory factor CD28 is found in metastases following biochemotherapy. These results indicate that parameters of importance for the immune function have already undergone modification after one or two treatment cycles and that this down-regulation occurs in particular in areas with regressive tumour changes.
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PMID:Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD28. 1235 21

Tumor cells are usually weakly immunogenic as they largely express self-antigens and can down-regulate major histocompatability complex/peptide molecules and critical costimulatory ligands. The challenge for immunotherapies has been to provide vigorous immune effector cells that circumvent these tumor escape mechanisms and eradicate established tumors. One promising approach is to engineer T cells with single-chain antibody receptors, and since T cells require 2 distinct signals for optimal activation, we have compared the therapeutic efficacy of erbB2-reactive chimeric receptors that contain either T-cell receptor zeta (TCR-zeta) or CD28/TCR-zeta signaling domains. We have demonstrated that primary mouse CD8(+) T lymphocytes expressing the single-chain Fv (scFv)-CD28-zeta receptor have a greater capacity to secrete Tc1 cytokines, induce T-cell proliferation, and inhibit established tumor growth and metastases in vivo. The suppression of established tumor burden by cytotoxic T cells expressing the CD28/TCR-zeta chimera was critically dependent upon their interferon gamma (IFN-gamma) secretion. Our study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen.
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PMID:Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. 1238 13

Activation of CTL-mediated antitumor immunity to self-epitopes expressed by neoplastic cells is thought to be prevented, at any stage of tumor progression, by tolerance mechanisms. In contrast, in 74 American Joint Committee on Cancer stages I-IV melanoma patients, we found that development of lymph node metastases is a key event triggering CD8(+) T-cell-mediated immunity to self-epitopes encoded by melanocyte differentiation antigens. This was shown by the increased peripheral precursor frequency to Melan-A/Mart-1, gp100, and tyrosinase epitopes in stage III and IV compared with stage I and II patients, and by accumulation of functional memory T cells directed to Melan-A/Mart-1(26-35) in tumor-invaded lymph nodes. However, in tumor-invaded lymph nodes of most patients, CD8(+) T cells directed to melanocyte differentiation antigens or to tumor-restricted antigens (MAGE-3 and NY-ESO-1 epitopes), showed a CCR7(+) CD45RA(+) CD27(+) CD28(+) perforin(-) "precursor" phenotype. Only in 7 of 23 cases antigen-specific CD8(+) T cells in invaded lymph nodes showed a predominant CCR7(-) CD45RA(-) CD27(+) CD28(-) perforin(+) "preterminally differentiated" phenotype. In the latter subset of patients, by immunohistochemistry in lymph node lesions, we found that CD8(+) T lymphocytes intermingling with the neoplastic tissue expressed a CCR7(-) CD45RO(+)/RA(-) phenotype, whereas CD4(+) lymphocytes did not infiltrate the tumor. Furthermore, perforin and granzyme B were expressed on a higher fraction of the CD8(+) cells surrounding the invading tumor compared with the lymphocytes infiltrating the neoplastic tissue. In addition, no evidence for tumor regression was found in such metastatic lesions, as documented by absence of neoplastic cell necrosis or apoptosis. These data indicate that neoplastic cells in the lymph nodes and/or increased tumor burden in metastatic disease activate CD8(+) T-cell-mediated antitumor immunity to self-epitopes. However, the paucity of terminally differentiated CD8(+) T cells at tumor site suggests that immunotherapy strategies may require not only the boosting of tumor immunity, but also effective means to promote CD8(+) T-cell differentiation in the neoplastic tissue.
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PMID:Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. 1275 Feb 77

Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an adoptive immunotherapy model. The number of pulmonary metastases was significantly reduced and survival was prolonged after the transfer of anti-CD3/anti-CD28/anti-4-1BB-activated TDLN cells compared with an equivalent number of cells activated without anti-4-1BB. The antitumor effect through 4-1BB involvement during CD28 costimulation was dependent on IFN-gamma production and abrogated after IFN-gamma neutralization. By contrast, interleukin 10 neutralization resulted in significantly enhanced tumor regression. These results indicate that costimulation of TDLN cells through newly induced 4-1BB and CD3/CD28 signaling can significantly increase antitumor reactivity by shifting T-cell responses toward a type 1 cytokine pattern while concomitantly decreasing type 2 responses.
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PMID:Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. 1275 Feb 78

Human epithelial mucin (MUC1) is expressed by many carcinomas, including breast cancer cells. This breast cancer-associated antigen has been widely used for immunotherapy, despite the fact that cellular immune responses to MUC1 are impaired in breast cancer patients and MUC1 transgenic animals. Previously, we found that immunogenicity to MUC1 was also impaired in BALB/c mice injected with a mammary tumor cell line (410.4) expressing human MUC1. We suggested that one reason for its weak immunogenicity was the lack of expression of B7 molecules by 410.4 cells. Recognition of antigenic epitopes in conjunction with MHCI/II by the T-cell receptor without co-stimulation by B7/CD28 association resulted in T-cell anergy. Therefore, we attempted to enhance protective anti-MUC1-specific immunity in mice using B7 co-stimulatory molecules as a component of the MUC1 vaccine. We also compared cell-based with DNA-based vaccination strategies. One group of mice was vaccinated with an irradiated, 410.4 syngeneic mammary tumor cell line co-expressing human MUC1 and CD80 or CD86 co-stimulatory molecules, and a second group of mice was vaccinated with plasmids encoding MUC1 and CD80 or CD86. These mice along with appropriate controls were challenged with mammary tumor cell line 4T1, which expresses MUC1. There were significant inhibition on rates of tumor growth and survival in mice vaccinated with irradiated 410.4/MUC1 cells co-expressing either CD80 or CD86 molecules, compared to non-vaccinated animals. In addition, there were also significant delays in the appearance of measurable tumors and their growth in mice vaccinated by gene-gun immunization with plasmids encoding MUC1 and CD80 or CD86.
Clin Exp Metastasis 2003
PMID:Immunization with a vaccine that combines the expression of MUC1 and B7 co-stimulatory molecules prolongs the survival of mice and delays the appearance of mouse mammary tumors. 1459 82

The purpose of this study was to test melanoma vaccines consisting of peptides and immunological adjuvants for optimal immunogenicity and to evaluate laboratory immune monitoring for in vivo relevance. Forty-nine HLA-A2 positive patients with Melan-A positive melanoma were repeatedly vaccinated with Melan-A peptide, with or without immune adjuvant AS02B (QS21 and MPL) or IFA. Peptide-specific CD8 T cells in PBLs were analyzed ex vivo using fluorescent HLA-A2/Melan-A multimers and IFN-gamma ELISPOT assays. The vaccines were well tolerated. In vivo expansion of Melan-A-specific CD8 T cells was observed in 13 patients (1/12 after vaccination with peptide in AS02B and 12/17 after vaccination with peptide in IFA). The T cells produced IFN-gamma and downregulated CD45RA and CD28. T-cell responses correlated with inflammatory skin reactions at vaccine injection sites (P < 0.001) and with DTH reaction to Melan-A peptide (P < 0.01). Twenty-six of 32 evaluable patients showed progressive disease, whereas 4 patients had stable disease. The two patients with the strongest Melan-A-specific T-cell responses experienced regression of metastases in skin, lymph nodes, and lung. We conclude that repeated vaccination with Melan-A peptide in IFA frequently leads to sustained responses of specific CD8 T cells that are detectable ex vivo and correlate with inflammatory skin reactions.
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PMID:Ex vivo detectable activation of Melan-A-specific T cells correlating with inflammatory skin reactions in melanoma patients vaccinated with peptides in IFA. 1514 68

We have shown previously that IFN-gamma-inducing cytokines such as IL-12 can mediate potent antitumor effects against murine solid tumors. IL-27 is a newly described IL-12-related cytokine that potentiates various aspects of T and/or NK cell function. We hypothesized that IL-27 might also mediate potent antitumor activity in vivo. TBJ neuroblastoma cells engineered to overexpress IL-27 demonstrated markedly delayed growth compared with control mice, and complete durable tumor regression was observed in >90% of mice bearing either s.c. or orthotopic intra-adrenal tumors, and 40% of mice bearing induced metastatic disease. The majority of mice cured of their original TBJ-IL-27 tumors were resistant to tumor rechallenge. Furthermore, TBJ-IL-27 tumors were heavily infiltrated by CD8(+) T cells, and draining lymph node-derived lymphocytes from mice bearing s.c. TBJ-IL-27 tumors are primed to proliferate more readily when cultured ex vivo with anti-CD3/anti-CD28 compared with lymphocytes from mice bearing control tumors, and to secrete higher levels of IFN-gamma. In addition, marked enhancement of local IFN-gamma gene expression and potent up-regulation of cell surface MHC class I expression are noted within TBJ-IL-27 tumors compared with control tumors. Functionally, these alterations occur in conjunction with the generation of tumor-specific CTL reactivity in mice bearing TBJ-IL-27 tumors, and the induction of tumor regression via mechanisms that are critically dependent on CD8(+), but not CD4(+) T cells or NK cells. Collectively, these studies suggest that IL-27 could be used therapeutically to potentiate the host antitumor immune response in patients with malignancy.
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PMID:IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells. 1558 38

We have previously described the antitumor reactivity of tumor-draining lymph node (TDLN) cells after secondary activation with antibodies. In this report, we examined the effects of interleukin (IL)-12 and IL-18 on modulating the immune function of antibody-activated murine TDLN cells. TDLN cells were activated with anti-CD3/anti-CD28 monoclonal antibody followed by stimulation with IL-12 and/or IL-18. IL-18 in combination with IL-12 showed a synergistic effect in augmenting IFNgamma and granulocyte macrophage colony-stimulating factor secretion, whereas IL-18 alone had minimal effect. Concurrently, IL-18 prevented IL-12-stimulated TDLN cells from producing IL-10. The IL-12/IL-18-cultured TDLN cells therefore manifested cytokine responses skewed towards a Th1/Tc1 pattern. IL-12 and IL-18 stimulated CD4(+) TDLN cells and enhanced IFNgamma production by CD4(+) cells to a greater extent than by CD8(+) cells. Use of NF-kappaB p50(-/-) TDLN cells suggested the involvement of NF-kappaB in the IL-12/IL-18 polarization effect. Furthermore, a specific NF-kappaB inhibitor significantly suppressed IL-12/IL-18-induced IFNgamma secretion, thus confirming the requirement for NF-kappaB activation in IL-12/IL-18 signaling. In adoptive immunotherapy, IL-12- and IL-18-cultured TDLN cells infiltrated pulmonary tumor nodules and eradicated established tumor metastases more efficiently than T cells generated with IL-12 or IL-18 alone. Antibody depletion revealed that both CD4(+) and CD8(+) cells were involved in the tumor rejection induced by IL-12/IL-18-cultured TDLN cells. These studies indicate that IL-12 and IL-18 can be used to generate potent CD4(+) and CD8(+) antitumor effector cells by synergistically polarizing antibody-activated TDLN cells towards a Th1 and Tc1 phenotype.
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PMID:Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. 1570 8

Cytotoxic T cells is an unique lymphocyte subpopulation able to recognize in specific manner and kill tumor cells. Therefore they constitute an important cells engaged in anti-tumor defense. The aim of the study was to determinate cytotoxic T cells frequency in peripheral blood and among lymphocytes isolated from regional lymph nodes. The study group consisted of twenty patients diagnosed with laryngeal cancer subjected surgical treatement. Cytotoxic T cells were estimated using three color flow cytometry based on CD3(+)CD8(+)CD28(-) GranzymeB(+) phenotype. Additionally TCR zeta chain expression and spontaneous apoptosis considered as a potential markers of immunosupressive effect exert by tumor were determined. In patients with laryngeal cancer significant increase of CD3(+)CD8(+)CD28(-) lymphocytes in peripheral blood in comparison to healthy control was observed. In lymph nodes the content of those cells was much lower, less than 10%, however in a group bearing metastases to regional lymph nodes higher than in a group without metastases. Cytotoxic T cells were also the main population subjected spontaneous apoptosis. The role and specificity of cytotoxic T cells in laryngeal cancer patients still remain to be elucidated, especially in respect to specificity of recognition tumor cell. Understanding details of this process may rise significant progress in an approach to diagnosis and therapy in laryngeal cancer patients.
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PMID:[Cytotoxic T lymphocytes in peripheral blood and regional lymph nodes in laryngeal cancer patients]. 1573 25


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