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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a new and apparently unique human lymphoma cell line termed Deglis. The line was established from a polymorphic centroblastic lymphoma. The cell line and its source carry a dual B-cell and T-cell phenotype and Epstein-Barr virus (EBV) genomes. Simultaneous expression of B-cell (CD19+, CD20+, CD23+, CD37+) and T-cell (CD2+, CD3+/-, CD7+, CD43+) antigens, activation antigens (CD30+, CDw70+) as well as CD68+, a macrophage-associated antigen, was observed on the cell line and its source. Genotypic studies of the cell line showed dual gene rearrangements. JH (on both primary tumor and the cell line) and C kappa were rearranged without expression of cytoplasmic or surface immunoglobulins. T-cell receptor-alpha (TCR-alpha) and TCR-beta genes were rearranged, but TCR-delta and TCR-gamma genes were in germline configuration. Apparently, functional transcripts of TCR-alpha and truncated transcripts for TCR-beta and TCR-delta were observed. EBV-encoded proteins (LMP and EBNA2) were expressed by the parent tumor and the cell line. Southern blot analysis showed the same clonal EBV genomes in the primary tumor and the cell line. Karyotypic analysis of the cell line showed several chromosomal abnormalities but normal chromosomal number. The characteristics of this cell line suggest that neoplastic transformation has occurred in a precursor cell broadly committed to lymphoid lineage. Further studies on this cell line may help resolve some issues in the physiopathology of lymphoid tumors.
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PMID:A novel human lymphoma cell line (Deglis) with dual B/T phenotype and gene rearrangements and containing Epstein-Barr virus genomes. 131 35

We studied the configuration and expression of the gene encoding the beta chain of the T cell receptor (TCR beta) in cell lines and primary tumor cells infected by the human T cell leukemia/lymphoma (lymphotrophic) virus type I (HTLV-I). Most of the cell lines and all the primary tumor cells showed rearrangement of the TCR beta gene, and in each case the rearrangement was distinct. The majority of cases examined were clonal with respect to a particular TCR beta gene rearrangement. Primary tumor cells from one case (SD) were found to have a tandem duplication of a portion of chromosome 7; this appears to have resulted in the presence of three alleles of the TCR beta gene, each of which is arranged differently. This suggests that the chromosomal abnormality, and possibly infection by HTLV-I, occurred before TCR beta gene rearrangement. Cell lines infected by HTLV-I express levels of TCR beta mRNA similar to PHA stimulated lymphocytes, suggesting that this gene is not transcriptionally activated as a result of infection by HTLV-I. Cloned T cells of known antigen specificity that are infected by HTLV-I in vitro show impairment of immune function, including loss of antigen-specific responsiveness and the acquisition of alloreactivity. Comparison of the configuration of the TCR beta gene before and after infection revealed no changes detectable by Southern blot analysis. Levels of expression of the TCR beta gene at the mRNA level and surface expression of the T3 complex were also not significantly altered, suggesting that changes in immune function cannot be attributed to quantitative changes in the TCR molecule. The configuration of the TCR beta gene in primary tumor cells infected by HTLV-I was compared with that in the derived cell lines. In all pairs examined, the configuration in the primary tumor cells was different from that in the cell lines, strongly suggesting that the cells that grow in culture are not the original neoplastic cells.
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PMID:Configuration and expression of the T cell receptor beta chain gene in human T-lymphotrophic virus I-infected cells. 300 26

Most tumors grow progressively and overwhelm the host. The rare but documented cases of spontaneous regression of primary tumors are indicative of the potential of tumor-bearing hosts to develop a significant antitumor response. Because most tumors grow progressively in the host, it is not surprising that the majority of studies have focused on T lymphocytes that infiltrate these tumors. Although these studies have generated significant and useful information during the period of tumor growth, they can only speculate on the mechanisms that are involved in tumor rejection. We have used a well developed sponge model of concomitant tumor immunity that allows us to compare the immunologic events that occur during tumor progression vs rejection. In this model, an animal harboring a primary EMT6 mammary tumor is challenged with a secondary tumor implant through a pre-implanted gelatin sponge. During the manifestation of concomitant tumor immunity, the secondary tumor is rejected and the effector cells mediating the response are retained within the sponge matrix. Using this model we analyzed the TCR usage, cytotoxic activity of lymphocytes, and cytokine production at both tumor sites. The data revealed that tumor-rejecting lymphocytes isolated from the site of secondary tumor implant were cytotoxic toward EMT6 cells, whereas tumor-infiltrating lymphocytes isolated from the progressing primary tumor were not. Interestingly, the TCR-V beta repertoire of the tumor-infiltrating lymphocytes and tumor-rejecting lymphocytes were identical with V beta 1 and V beta 8 being predominant at both sites. Furthermore, the rejection site showed higher gene expression of IFN-gamma, TNF-alpha, and IL-10 whereas TGF-beta expression was slightly higher in the progressing tumors. These findings suggest that the disparate effector functions observed during tumor progression vs rejection are not caused by different T cell phenotypes but may be due instead to influences exerted by cytokines produced at the tumor sites.
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PMID:T lymphocytes infiltrating sites of tumor rejection and progression display identical V beta usage but different cytotoxic activities. 770 35

A subset of patients with non-Hodgkin's lymphoma (NHL), present with or subsequently develop lymphocytic effusions. Differential diagnosis between reactive lymphocytosis and recurrent low-grade NHL is difficult by cytology alone. We studied the use of polymerase chain reaction (PCR)-based techniques to detect concurrent/recurrent NHL. Both primary tumors and atypical lymphocytic effusions of 12 low-grade B-NHL patients and 4 T-NHL patients were studied. Six pleural effusions (reactive/carcinomatous), in patients with no history of NHL, were included. Samples were amplified by PCR, using Fr3, Fr2, LJH, and VLJH primers specific for the immunoglobulin heavy chain (IgH) gene and Vgamma-8, Vgamma9, Vgamma10, Vgamma11 and Jgamma1/Jgamma2 consensus primers specific for the T-cell receptor gamma (TCR-gamma) gene. IgH gene PCR products were analyzed by polyacrylamide gel electrophoresis (PAGE). TCR-gamma gene PCR products were analyzed using a novel nonradioactive single-strand conformational polymorphism (SSCP) procedure. IgH gene rearrangement analysis demonstrated monoclonality in 11/12 primary low-grade B-NHLs. Identical monoclonal bands were found in both primary tumor and effusion in 9 patients. TCR-gamma gene rearrangement analysis demonstrated monoclonality in 4 of 4 primary T-NHLs. Identical monoclonal banded patterns were found in both primary tumor and effusion in 3 patients. Our results strongly support the diagnosis of concurrent/recurrent NHL in 13 of 16 (81%) cases of atypical lymphocytic effusions. IgH/PAGE and TCR-gamma/SSCP analyses are useful tools in the diagnoses of lymphocytic effusions in patients with NHL.
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PMID:Detection of concurrent/recurrent non-Hodgkin's lymphoma in effusions by PCR. 1057 18

CD8 T cell-mediated immune responses fall into two distinct types based on effector cell-derived cytokine production. Type I CD8 T cells (Tc1) produce IFN-gamma, whereas type 2 cells (Tc2) secrete IL-4, IL-5, IL-10, and GM-CSF. Using a murine TCR transgenic T cell/breast tumor model, we show that adoptively transferred Ag-specific Tc1 cells are more effective in delaying mammary tumor growth and progression than that of functionally distinct Tc2 cells. Donor Tc1 cells administered 7 days posttumor challenge localized and persisted at sites of primary tumor growth with antitumor responses that were dependent, in part, on effector cell-derived IFN-gamma. Tc1-mediated responses markedly enhanced the appearance and local accumulation of highly differentiated (CD44(high)) CD4 and CD8 endogenous tumor-infiltrating T cells when compared with that of untreated tumor-bearing mice. Conversely, Tc1 cell transfer markedly delayed the appearance of corresponding nondifferentiated (CD44(low)) endogenous T cells. Such cells were acutely activated as defined by coexpression of surface markers associated with TCR engagement (CD69) and early T cell activation (CD25). Moreover, cellular response kinetics appeared to further correlate with the up-regulation of endogenous T cells producing the chemokine IFN-gamma-inducible protein-10 in vivo. This suggested that CD8-mediated type 1 antitumor responses cannot only promote accumulation of distinct endogenous CD4 and CD8 T cell subpopulations, but also facilitate and preferentially modulate their localization kinetics, persistence, states of activation/differentiation, and function within the primary tumor environment at various stages of tumor progression. These studies offer insight into potential mechanisms for enhancing T cell-based immunotherapy in breast cancer.
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PMID:CD8-mediated type 1 antitumor responses selectively modulate endogenous differentiated and nondifferentiated T cell localization, activation, and function in progressive breast cancer. 1711 96

Cell-based immunotherapy in settings of allogeneic stem cell transplantation or donor leukocyte infusion has curative potential, especially in hematologic malignancies. However, this approach is severely restricted due to graft-versus-host disease (GvHD). This limitation may be overcome if target antigens are molecularly defined and effector cells are specifically selected. We chose formin-related protein in leukocytes 1 (FMNL1) as a target antigen after intensive investigation of its expression profile at the mRNA and protein levels. Here, we confirm restricted expression in peripheral blood mononuclear cells (PBMCs) from healthy donors but also observe overexpression in different leukemias and aberrant expression in transformed cell lines derived from solid tumors. We isolated allorestricted T-cell clones expressing a single defined TCR recognizing a particular HLA-A2-presented peptide derived from FMNL1. This T-cell clone showed potent antitumor activity against lymphoma and renal cell carcinoma cell lines, Epstein-Barr virus (EBV)-transformed B cells, and primary tumor samples derived from patients with chronic lymphocytic leukemia (CLL), whereas nontransformed cells with the exception of activated B cells were only marginally recognized. Allorestricted TCRs with specificity for naturally presented FMNL1-derived epitopes may represent promising reagents for the development of adoptive therapies in lymphoma and other malignant diseases.
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PMID:Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies. 1762 42

The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered 3 days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated donor TIL cells. This markedly enhanced the appearance of endogenous differentiated (CD44(High)) CD8 tumor-infiltrating cells when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Such cells were acutely activated as defined by co-expression of surface markers associated with TCR engagement (CD69) and T cell activation (CD25) at both early (days 1-8) and late (days 12-20) stages following treatment. Conversely, such animals showed an early decrease in CD4(+)/CD44(High)/CD25(+)/CD69(+) T cells that correlated with delays in tumor growth in vivo. Moreover, cellular response kinetics appeared to further correlate with the up-regulation of endogenous T cells producing the chemokine IP-10 in vivo. This suggested that Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating immunoregulatory T cells involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer.
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PMID:Ag-specific type 1 CD8 effector cells enhance methotrexate-mediated antitumor responses by modulating differentiated T cell localization, activation and chemokine production in established breast cancer. 1851 46

The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with Ag-specific T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose-treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered three days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated CD25(+) expressing donor TIL cells. This correlated with a marked decrease in the appearance of endogenous differentiated (CD44(High)) CD3/CD8/CD49b and CD3/CD4/CD49b tumor-infiltrating effector T cells at both early (Days 1-8) and late (Days 12-20) stages following treatment when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Moreover, such cellular response kinetics appeared to further correlate with the down-regulation of endogenous CD4/CD44(High)/CD49b effector T cells producing IL-10 and delays in tumor growth in vivo. This suggested that Ag-specific Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating select CD49b-expressing T effector/memory cell subpopulations involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer. Supplementary materials are available for this article. Go to the publisher's online edition of Immunological Investigations for the following free supplemental resource(s): Addendum 1.
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PMID:Ag-specific type 1 CD8 effector cells enhance methotrexate-mediated antitumor responses by modulating endogenous CD49b-expressing CD4 and CD8 T effector cell subpopulations producing IL-10. 1856 73

Tumor infiltrating lymphocytes (TIL) cultured long term in media containing IL-2 were shown to mediate in vitro and in vivo anti-tumor responses. To understand the anti-tumor activity of TIL T cells, we used polymerase chain reaction (PCR) to characterize the TCR Vbeta repertoire of ovarian TIL which were isolated from three tumor sites of the same patient at the same time and cultured under identical conditions, resulting in CD3+ cells with similar CD8:CD4 ratios. TIL isolated from ovary and ascites expressed a broad distribution of Vbeta repertoire, while the Vbeta phenotype of the TIL from a secondary tumor (omentum) was more restricted. After 5 months, cultured TIL from the primary tumor (ovary) maintained a diverse TCR Vbeta repertoire, but the Vbeta phenotype of TIL from the secondary site was dominated by the Vbeta-1, -11 and -14 families. Importantly, the percentages of Vbeta-11 and Vbeta-1 expression in both omentum and ovary TIL at 3 and 5 months was found to correlate with the levels of lysis of the tumor localized to omentum (p =0.003 and p=0.014, respectively). No statistical correlation was found between cytotoxicity and the use of any other individual Vbeta families or the sum of any other families, including TCR Vbeta-3 or -20 found increased at certain time points. This suggests that where certain TCR Vbeta families are selected in tumor reactive T cells this selection may reflect tumor Ag recognition at either primary or distant tumor sites. To our knowledge, this is the first documentation of complete TCR Vbeta repertoire of ovarian TIL and of a correlation between Vbeta usage and tumor lysis, by effectors from different sites.
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PMID:Dissimilar tcr v-Beta frequencies in til from different sites of the same tumor. 2157 81

Balancing the potential for durable remissions with autoimmune-like toxicities is a key clinical challenge in the use of immune checkpoint inhibitors (ICI). Certain toxicities are associated with an increased response rate; however, the molecular underpinnings of this association are poorly understood. Here, we report a patient with wide spread uveal melanoma who had an exceptional response to treatment with ipilimumab and nivolumab, but suffered severe immune-related sequelae, including central serous retinopathy with retinal detachment, tinnitus, and vitiligo resembling Vogt-Koyanagi-Harada disease, and refractory enteritis. TCR-sequencing of the primary tumor, a hepatic metastasis, duodenal biopsy and peripheral blood mononuclear cells, identified the identical T cell clone in all four tissues. This case provides preliminary evidence for cross-reactivity as a mechanism for the association between effect and toxicity of ICIs.
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PMID:Exceptional response and multisystem autoimmune-like toxicities associated with the same T cell clone in a patient with uveal melanoma treated with immune checkpoint inhibitors. 3083 16


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