Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The membrane receptor 2B4 is a CD2 family member that is involved in lymphocyte activation. A fraction of human CD8+ alphabeta T cells up-regulate 2B4 in vivo, and here we demonstrate that this correlates with the acquisition of effector cell properties such as granzyme B and perforin expression, rapid IFN-gamma production, and down-regulation of the lymph node homing chemokine receptor CCR7. In PBLs from healthy donors, cytomegalovirus-specific effector T cells were 2B4 positive, whereas naive melanoma Ag (Melan-A/melanoma Ag recognized by T cells-1)-specific T cells were 2B4 negative. In melanoma patients, Melan-A-specific T cells up-regulated 2B4 in parallel with in vivo differentiation. This occurred in PBLs after vaccination with Melan-A peptides and in tumor-infiltrated lymph nodes, likely through disease-associated activation of Melan-A-specific T cells. Thus, 2B4 expression correlates with CD8+ T cell differentiation in vivo.
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PMID:The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells. 1171 76

Testicular seminoma is characterized by a prominent lymphoid infiltrate and an excellent prognosis. Cytotoxic T-lymphocytes (CTLs) infiltrating seminoma tumour nests constitute a major subset of the lymphoid infiltrate. The objective of this study was to determine whether CTLs express markers of cytotoxic potential and activity and whether the number of activated CTLs correlates with the extent of apoptosis in testicular seminomas, as opposed to non-seminomatous testicular germ cell tumours (NSTGCTs). Twenty cases of pure seminoma as well as 20 cases of NSTGCTs including 16 mixed germ cell tumours (MGCTs) were studied. Immunohistochemistry for the cytotoxic markers TIA-1 (cytotoxic potential) and granzyme B (cytotoxic activity) and the T-cell markers CD3 and CD8 was performed on formalin-fixed, paraffin-embedded sections. The apoptotic index (AI) was determined by the TUNEL method. The number of CD3(+), CD8(+), TIA-1(+), and granzyme B(+) cells in tumour cell nests was markedly increased in testicular seminomas, compared with NSTGCTs (p<0.01). Activated granzyme B(+) cells numbered 25.6+/-5.2 per high power field in seminomas and 8.9+/-3.2, 8.1+/-3.9, and 0.4+/-0.2 for embryonal carcinomas, yolk sac tumours, and immature teratomas, respectively. Double immunohistochemical staining for granzyme B and CD8 revealed that 82.6+/-8.5% of granzyme B-expressing cells were CD8(+). The tumour cell AI was significantly increased in embryonal carcinoma, compared with the seminoma, yolk sac tumour, and immature teratoma subgroups (6.7+/-1.3, 2.3+/-0.3, 3.0+/-1.1, and 2.3+/-1.1, respectively, p<0.001). TUNEL/CD3 double immunostaining revealed that a significant proportion of the apoptotic seminomatous tumour cells were in direct contact with one or more CD3(+) lymphocytes (47.2+/-6.2%). The number of activated granzyme B(+) CTLs showed a strong linear correlation with the AI in the seminoma group (r=0.71, p<0.0001) but not in other subgroups. TUNEL/granzyme B double immunolabelling revealed that a proportion of activated granzyme B(+) lymphocytes (20%) were often seen in close contact with apoptotic tumour cells. The presence of increased numbers of activated cytotoxic lymphocytes in testicular seminomas suggests that apoptotic tumour cell death in this neoplasm may be triggered by cytotoxic granule effectors. This phenomenon may be one of the key host immune mechanisms leading to the excellent prognosis in this tumour.
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PMID:Activated status of tumour-infiltrating lymphocytes and apoptosis in testicular seminoma. 1174 44

In tumor cells, the serine protease granzyme B is the primary mediator of apoptosis induced by cytotoxic T lymphocytes (CTLs)/natural killer (NK) cells. The human intracellular serpin proteinase inhibitor 9 (PI9) is the only known human protein able to inhibit the proteolytic activity of granzyme B. When present in the cytoplasm of T lymphocytes, PI9 is thought to protect CTLs against apoptosis induced by their own misdirected granzyme B. Based on the speculation that tumors may also express PI9 to escape CTL/NK cell surveillance, immunohistochemical studies on the expression of PI9 in various lymphomas were performed. Ninety-two cases of T-cell non-Hodgkin lymphoma (NHL), 75 cases of B-cell NHL, and 57 cases of Hodgkin lymphomas were stained with a PI9-specific monoclonal antibody. In T-cell NHL, highest PI9 expression was found in the extranodal T-cell NHL. In nearly 90% of enteropathy-type T-cell NHLs and 80% of NK/T-cell, nasal-type lymphomas, the majority of the tumor cells expressed PI9. In nodal T-anaplastic large cell lymphomas and peripheral T-cell lymphomas (not otherwise specified), PI9 expression occurred less frequently. In B-cell NHL, PI9 expression was associated with high-grade malignancy; 43% of diffuse large B-cell lymphomas showed PI9(+) tumor cells. Finally, PI9 expression was also found in 10% of Hodgkin lymphomas. This is the first report describing the expression of the granzyme B inhibitor PI9 in human neoplastic cells in vivo. Expression of this inhibitor is yet another mechanism used by tumor cells to escape their elimination by cytotoxic lymphocytes.
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PMID:Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to circumvent the immune system? 1175 76

Serine proteinase inhibitor 9 (PI-9) inhibits granzyme B-mediated apoptosis and interleukin-1beta-converting enzyme activity. In this study, we report that the PI-9 gene encodes antigenic epitopes recognized by the HLA-A24-restricted and tumor-reactive cytotoxic T lymphocytes (CTLs) of epithelial cancer patients. Screening of an autologous cDNA library using a CTL line recognizing HLA-A24+ tumor cells resulted in the isolation of a cDNA, which had an identical coding region to the previously described PI-9 genes. PI-9 gene was expressed in approximately three-fourths of epithelial cancer cell lines and all leukemic cell lines tested. It was also expressed in normal peripheral blood mononuclear cells (PBMCs), but not in a normal fibroblast cell line. CTL sublines contained T cells capable of recognizing the PI-9(292-300) and PI-9(348-356) peptides among 13 different peptides having the HLA-A24 binding motifs. These two peptides were recognized by the CTL line in a dose-dependent and HLA class-I-restricted manner, and also possessed the ability to induce HLA class I-restricted and tumor-reactive CTLs in PBMCs from HLA-A24+ cancer patients. These results demonstrate that PI-9 is recognized by HLA class I-restricted and tumor-reactive CTLs of epithelial cancer patients.
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PMID:Serine proteinase inhibitor 9 can be recognized by cytotoxic T lymphocytes of epithelial cancer patients. 1185 84

Tumor immunity requires the participation of lymphocyte effector cells that display powerful processes to destroy malignant cells. Natural killer (NK) cells and CTLs, once activated, use the same lytic processes for mediating target cell death. However, they are triggered through distinctly separate antigen receptors. NK cells are currently known to express at least three families of receptors unrelated to the T cell receptor, i.e., NKG2, KIR, and NCR, to mediate cytotoxicity. This review provides a view to a kill, bringing together a unifying concept for a common signal pathway that dictates lytic function. What emerges is a specific Syk/Zap70 --> PI3K --> Rac --> PAK --> MEK --> ERK signal cascade triggered by target cell recognition, which is responsible for mobilizing the lytic granules containing perforin and granzyme B toward the contacted target cell.
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PMID:A view to a kill: signals triggering cytotoxicity. 1189 90

L82, a novel anaplastic large cell lymphoma (ALCL) cell line was established from the pleural effusion of a 24-year-old patient with recurrent ALCL. L82 cells showed the typical morphologic features of ALCL cells with irregular, often indented, nuclear profiles, prominent nucleoli, and abundant cytoplasm. The immunoprofile of L82 corresponds to that seen typically in primary ALCL cells, with positivity for CD30, EMA, CD3, CD4, CD25, CD71, TIA1, and granzyme B; the cells were negative for EBV-related antigens. Cytogenetic analysis showed a complex, near triploid karyotype with 72-77 chromosomes, including the ALCL specific translocation t(2;5)(p23;q35). Chromosomal analysis revealed a number of secondary structural alterations including amplification of 7q21-31, 1q, and 6p, and gain of chromosomal material in 8q (affecting the c-myc gene). The rearrangement of the T-cell receptor-gamma locus shows that L82 is clonally derived from T-lineage lymphoid cells. mRNAs for interleukin 7 (IL-7), IL-8, IL-9, IL-10, TNF-beta, and for the IL-7 and IL-9 receptor were found. These data show that the T-helper cell (Th)1/Th2 balance was polarized to Th2. L82 were inoculated intraperitoneally into 4 week-old SCID mice and produced a disseminated tumor within 4-6 weeks. Morphological, immunohistochemical, and molecular genetic investigation confirmed that the xenograft and the original ALCL tumor were identical. SCID mice xenografted with the human ALCL cell line, L82, provide a useful model system for the investigation of the biology of ALCL and of new therapeutic approaches, such as specific immunotherapy.
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PMID:Characterization of a novel human anaplastic large cell lymphoma cell line tumorigenic in SCID mice. 1190 23

In previous studies CD8+ T cells specific for melanocyte antigens have been frequently found in melanoma patients responding to interleukin-2 (IL-2)-based therapies. In our study we analyzed the suitability of using circulating T cells from melanoma patients with clinical response after IL-2-based therapy to identify novel T-cell epitopes from defined tumor antigens. Using unstimulated peripheral blood mononuclear cells and the interferon-gamma (IFN-gamma) ELISPOT assay, we studied CD8(+) T-cell responses against 5 peptides from the tumor antigen tyrosinase (Tyr) selected by epitope prediction using an HLA-A1-binding computer algorithm. T cells specifically secreting IFN-gamma in response to 3 of these 5 peptides, namely, Tyr (454-463), Tyr (146-156) and Tyr (243-251), could be detected in 4 of 4 HLA-A1-positive patients with clinical response. In contrast, no T-cell responses against these peptides were seen in 6 HLA-A1-positive melanoma patients with progressive disease and in 8 healthy subjects. We could generate specific cytotoxic T lymphocytes (CTL) against Tyr (454-463) using peptide-pulsed autologous dendritic cells as antigen-presenting cells. The induced CTLs efficiently killed melanoma cells that express HLA-A1 and tyrosinase. The peptides Tyr (146-156) and Tyr (243-251) had recently been identified as CTL epitopes by other groups. Further ex vivo characterization of the T cells reactive against the novel epitope Tyr (454-463) in 1 patient by multicolor flow cytometry showed specific CD3+/CD8+/IFN-gamma+ T cells with frequencies of up to 0.41% of the CD3+/CD8+ T-cell population. Most of this T-cell population also expressed granzyme B. Our data confirm that in patients with tumor regressions induced by immunotherapy or chemoimmunotherapy circulating T cells reactive with tyrosinase epitopes can frequently be detected. Peripheral blood T cells from such patients are a valuable source for screening peptides selected by epitope prediction This strategy facilitates the rapid identification of immunogenic T-cell epitopes that are probable targets of immune-mediated tumor rejection.
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PMID:Identification of known and novel immunogenic T-cell epitopes from tumor antigens recognized by peripheral blood T cells from patients responding to IL-2-based treatment. 1192 May 92

Multidrug resistance (MDR) mediated by the ATP-dependent efflux protein P-glycoprotein (P-gp) is a major obstacle to the successful treatment of many cancers. In addition to effluxing toxins, P-gp has been shown to protect tumor cells against caspase-dependent apoptosis mediated by Fas and tumor necrosis factor receptor (TNFR) ligation, serum starvation and ultraviolet (UV) irradiation. However, P-gp does not protect against caspase-independent cell death mediated by granzyme B or pore-forming proteins (perforin, pneumolysin and activated complement). We examined the effects of the chemotherapeutic hybrid polar compound suberoylanilide hydroxamic acid (SAHA) on P-gp-expressing MDR human tumor cell lines. In the CEM T-cell line, SAHA, a histone deacetylase inhibitor, induced equivalent death in P-gp-positive cells compared with P-gp-negative cells. Cell death was marked by the caspase-independent release of cytochrome c, reactive oxygen species (ROS) production and Bid cleavage that was not affected by P-gp expression. However, consistent with our previous findings, SAHA-induced caspase activation was inhibited in P-gp-expressing cells. These data provide evidence that P-gp inhibits caspase activation after chemotherapeutic drug treatment and demonstrates that SAHA may be of value for the treatment of P-gp-expressing MDR cancers.
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PMID:Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells. 1197 47

Adenosine, a purine nucleoside found at high levels in solid tumors, is able to suppress the recognition/adhesion and effector phases of killer lymphocyte-mediated tumor cell destruction. Here, we demonstrate that adenosine, at concentrations that are typically present in the extracellular fluid of solid tumors, exerts a profound inhibitory effect on the induction of mouse cytotoxic T cells, without substantially affecting T-cell viability. T-cell proliferation in response to mitogenic anti-CD3 antibody was impaired in the presence of 10 microM adenosine (plus coformycin to inhibit endogenous adenosine deaminase). Antigen-specific T-cell proliferation was similarly inhibited by adenosine. Anti-CD3-activated killer T (AK-T) cells induced in the presence of adenosine exhibited reduced major histocompatibility complex-unrestricted cytotoxicity against P815 mastocytoma cells in JAM and (51)Cr-release assays. Diminished tumoricidal activity correlated with reduced expression of mRNAs coding for granzyme B, perforin, Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as well as with diminished Nalpha-CBZ-L-lysine thiobenzylester (BLT) esterase activity. Interleukin-2 and interferon-gamma synthesis by AK-T cells was also inhibited by adenosine. AK-T cells express mRNA coding for A(2A), A(2B) and A(3) receptors, but little or no mRNA coding for A(1) receptors. The inhibitory effect of adenosine on AK-T cell proliferation was blocked by an A(3) receptor antagonist (MRS1191) but not by an A(2) receptor antagonist (3,7-dimethyl-1-propargylxanthine [DMPX]). The A(3) receptor agonists (N(6)-2-(4-aminophenyl)ethyladenosine [APNEA] and N(6)-benzyl-5'-N-ethylcarboxamidoadenosine [N(6)-benzyl-NECA]) also inhibited AK-T cell proliferation. Adenosine, therefore, acts through an A(3) receptor to prevent AK-T cell induction. Tumor-associated adenosine may act through the same mechanism to impair the development of tumor-reactive T cells in cancer patients.
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PMID:Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells. 1199 7

We report here on 2 patients who received adjuvant vaccination with an HLA-A2- or HLA-A24-restricted tyrosinase peptide, respectively, and GM-CSF for frequently relapsing stage IV melanoma. Following resection of metastases and irradiation of brain metastases in 1 patient, both patients were without evidence of disease when receiving the first vaccination. While the patients had had 9 and 12, respectively, mostly s.c., relapses during the 3 years before vaccination, they experienced freedom from relapse for more than 2 years after vaccination. We found a T-cell response to the vaccine peptide in both patients in the peripheral blood by ex vivo IFN-gamma ELISPOT assay. The T-cell population could be further characterized by 4-color flow cytometry in 1 patient, showing that the majority of the peptide-specific CD3(+)CD8(+)IFN-gamma(+) T cells were granzyme B-positive and CCR-7-negative, characterizing them as effector T cells with the ability to mediate cytotoxicity and migrate to inflamed tissues. In this patient also, augmentation of the T-cell response to autologous tumor cells by vaccination could be detected. A single-site postvaccination relapse occurred in both patients, showing downregulation of tyrosinase expression in 1 patient, while normal expression levels for tyrosinase, MHC class I antigens and components of the antigen-processing machinery were found in the other patient. These results suggest that peptide vaccination resulted in a prolonged relapse-free interval in these high-risk patients.
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PMID:Long-term freedom from recurrence in 2 stage IV melanoma patients following vaccination with tyrosinase peptides. 1199 9


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