Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function and activation requirements for gamma delta T cells residing in the human intestine are still poorly defined. We have established two gamma delta + T cell tumor-infiltrating lymphocyte (TIL) lines derived from a primary colorectal cancer (gamma delta TIL No. 3481), and from a colorectal cancer lesion metastatic to the liver (gamma delta TIL No. 7279). Both gamma delta TIL lines used exclusively the V delta 1 segment and predominantly the V gamma 2 segments of the T cell receptor (TCR) variable regions and lysed allogeneic colorectal cancer cell lines, e.g. HCT 116, but not natural killer/lymphokine-activated-killer-sensitive target cell lines, e.g. K562 or Daudi. gamma delta T cell effector functions were evaluated on the basis of their recognition and cytolysis of colorectal cancer cell lines, T cell proliferation, and interferon (IFN)-gamma release. Both gamma delta T cell lines exhibited similar responses to the staphylococcal superantigens (SE) A and B. SEA and SEB did not influence target cell cytolysis of colon cancer targets. Neither gamma delta + T cell line responded to SEA as measured by IFN-gamma release of T cell proliferation. In marked contrast, SEB induced T cell proliferation and IFN-gamma release in the absence of stimulator cells. SEB induced secretion of IFN-gamma by gamma delta T cells which could be augmented if stimulator cells (HCT116) were also added to gamma delta T cells. On the basis of these data, we suggest that intestine-derived V delta 1/V gamma 2+ T cells respond preferentially to SEB and not to SEA. This disparity may reflect the inherently higher affinity of individual gamma delta TCR subsets for SEB but not to SEA and/or indicate that a subset of gamma delta + TILs in patients with colon cancer may be preferentially expanded with a TCR rearrangement favoring the interaction with SEB. The induction of IFN-gamma release and proliferative gamma delta + T cell responses by SEB suggests a pivotal role for intestinal gamma delta T cells in mediating immune responses against bacteria and bacterial products, or potentially in anti-tumor-directed immunity. Such immune responses mediated by gamma delta + T cells may take place prior to the maturation of antigen-specific MHC-restricted alpha beta + T cell responses.
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PMID:Human intestinal V delta 1+ T cells obtained from patients with colon cancer respond exclusively to SEB but not to SEA. 869 8

A chimeric immune receptor consisting of an extracellular antigen-binding domain derived from the CC49 humanized single-chain antibody, linked to the CD3zeta signaling domain of the T cell receptor, was generated (CC49-zeta). This receptor binds to TAG-72, a mucin antigen expressed by most human adenocarcinomas. CC49-zeta was expressed in CD4+ and CD8+ T cells and induced cytokine production on stimulation. Human T cells expressing CC49-zeta recognized and killed tumor cell lines and primary tumor cells expressing TAG-72. CC49-zeta T cells did not mediate bystander killing of TAG-72-negative cells. In addition, CC49-zeta T cells not only killed FasL-positive tumor cells in vitro and in vivo, but also survived in their presence, and were immunoprotective in intraperitoneal and subcutaneous murine tumor xenograft models with TAG-72-positive human tumor cells. Finally, receptor-positive T cells were still effective in killing TAG-72-positive targets in the presence of physiological levels of soluble TAG-72, and did not induce killing of TAG-72-negative cells under the same conditions. This approach is being currently being utilized in a phase I clinical trial for the treatment of colon cancer.
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PMID:Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor. 1002 40

A promising strategy for cancer treatment is adoptive immunotherapy with gene-modified lymphocytes expressing a chimeric T cell receptor (cTCR) that directs tumor targeting and stimulates T cell effector functions. In this study, the activities of two novel cTCR molecules (GAgamma and GAHgamma) were investigated. Both encode a single-chain variable fragment (scFv) derived from the monoclonal antibody (MAb) GA733.2, which binds the epithelial glycoprotein 2 (EGP-2) overexpressed on a variety of human carcinomas. In the GAgamma cTCR, the scFv is directly fused to the transmembrane/cytoplasmic portions of the immunoglobulin Fc receptor (Ig FcRI) gamma subunit, which mediates T cell signaling. GAHgamma possesses an extracellular spacer composed of the CD8alpha immunoglobulin hingelike domain inserted between the scFv and gamma chain. Activated T cells (ATCs), stimulated ex vivo using anti-CD3 MAb, were derived from either healthy donors or patients and transduced with recombinant retrovirus encoding the respective GA cTCR molecules. After culture expansion for 14 days, GAgamma-modified ATCs demonstrated enhanced targeting and lysis of EGP-2+ colon cancer cells and increased cytokine secretion. Cells transduced with the GAHgamma cTCR displayed specific lytic activity that was about twofold greater than that of GAgamma-ATCs and produced significantly more cytokine. In addition, reactivation of GAHgamma-ATC with anti-CD3 MAb prior to addition to EGP-2+ tumor target induced a further increase in lytic activity. Because the activation status influences T cell antitumor functions, our data suggest that reactivation prior to adoptive transfer would improve the clinical efficacy of GAHgamma-modified ATCs.
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PMID:Specific targeting of EGP-2+ tumor cells by primary lymphocytes modified with chimeric T cell receptors. 1064 35

The current objective of our cancer programme is to develop an effective vaccine based on rationally designed T cell epitope analogues, for use in the adjuvant setting for non-small cell lung cancer (NSCLC) and colon cancer. Analogue epitopes, enhanced for either human leukocyte antigen (HLA) binding or T cell receptor (TCR) signalling, have been shown to be more effective at breaking immunological tolerance than cognate wild-type epitopes. Although encouraging early-phase clinical data has been obtained by others using a limited number of HLA-A2-restricted epitope analogues, the clinical benefits and immune correlates for vaccines comprised of multiple epitope analogues restricted by multiple HLA supertypes remains to be investigated. Clinical studies are currently being conducted on EP-2101, a prototype vaccine that delivers multiple HLA-A2-restricted analogue epitopes. In parallel, fixed anchor and heteroclitic analogues restricted by three other commonly expressed HLA supertypes are being identified. These analogues will be incorporated into future vaccines including optimised minigenes (epigenes) and tested in preclinical and clinical studies addressing various different cancer indications.
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PMID:Design of multi-epitope, analogue-based cancer vaccines. 1294 57

BACKGROUND: alpha-Galactosylceramide (alpha-GalCer) can be presented by CD1d molecules of antigen-presenting cells, and is known to induce a potent NKT cell-dependent cytotoxic response against tumor cells. However, the main effector cells in alpha-GalCer-induced antitumor immunity are still controversial. METHODS: In order to elucidate the cell phenotype that plays the most important role in alpha-GalCer-induced antitumor immunity, we purified and analyzed tumor-infiltrating leukocytes (TILs) from liver metastatic nodules of a colon cancer cell line (Colon26), comparing alpha-GalCer- and control vehicle-treated mice. Flow cytometry was performed to analyze cell phenotype in TILs and IFN-gamma ELISA was performed to detect antigen-specific immune response. RESULTS: Flow cytometry analysis showed a significantly higher infiltration of NK cells (DX5+, T cell receptor alphabeta (TCR)-) into tumors in alpha-GalCer-treated mice compared to vehicle-treated mice. The DX5+TCR+ cell population was not significantly different between these two groups, indicating that these cells were not the main effector cells. Interestingly, the CD8+ T cell population was increased in TILs of alpha-GalCer-treated mice, and the activation level of these cells based on CD69 expression was higher than that in vehicle-treated mice. Moreover, the number of tumor-infiltrating dendritic cells (DCs) was increased in alpha-GalCer-treated mice. IFN-gamma ELISA showed stronger antigen-specific response in TILs from alpha-GalCer-treated mice compared to those from vehicle-treated mice, although the difference between these two groups was not significant. CONCLUSIONS: In alpha-GalCer-induced antitumor immunity, NK cells seem to be some of the main effector cells and both CD8+ T cells and DCs, which are related to acquired immunity, might also play important roles in this antitumor immune response. These results suggest that alpha-GalCer has a multifunctional role in modulation of the immune response.
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PMID:Tumor-infiltrating effector cells of alpha-galactosylceramide-induced antitumor immunity in metastatic liver tumor. 1525 Oct 43

Loss of the adenomatous polyposis coli (APC) protein is a common initiating event in colon cancer. Here we show that thymocyte-specific loss of APC deregulated beta-catenin signaling and suppressed Notch-dependent transcription. These events promoted the proliferation of cells of the double-negative 3 and 4 stages and reduced rearrangements between the variable, diversity and joining regions of the gene encoding T cell receptor (TCR) beta, encouraging developmental progression of aberrant thymocytes lacking pre-TCR and alphabeta TCR. Simultaneously, the loss of APC prolonged the mitotic metaphase-to-anaphase checkpoint and impaired chromosome segregation, blocking development beyond the double-negative 4 stage. The result was extensive thymic atrophy and increased frequencies of thymocytes with chromosomal abnormalities. Thus, loss of APC in immature thymocytes has consequences distinct from those of deregulation of beta-catenin signaling and is essential for T cell differentiation.
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PMID:Loss of adenomatous polyposis coli gene function disrupts thymic development. 1602 18

Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infiltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infiltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.
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PMID:Colon cancer and the immune system: the role of tumor invading T cells. 1714 36

We previously reported that Tespa1 (thymocyte-expressed, positive selection-associated gene 1) protein expressed in lymphocytes physically interacts with IP3R (Inositol 1,4,5-trisphosphate receptor), a Ca(2+) channel protein spanning endoplasmic reticulum (ER) membrane. However, the biochemical characterization of Tespa1 protein remains unknown. In this study, we have found that Tespa1 protein was posttranslationally modified upon intracellular Ca(2+) increase in thymocytes. Through the analyses using various inhibitors, store-operated Ca(2+) entry (SOCE) was found to be an essential factor for the Tespa1 protein modification induced by T cell receptor (TCR)-stimulation. Remarkably, the Ca(2+)-dependent Tespa1 protein modification was restored by in vitro protein phosphatase treatment, indicating that this modification was due to phosphorylation. Moreover, we examined whether Ca(2+)-dependent phosphorylation of Tespa1 protein would affect the physical association between Tespa1 and IP3R proteins, revealing that physical association of these proteins is maintained regardless of the presence or absence of phosphorylation of Tespa1. In addition, KRAP protein which represents substantial amino acid sequence homology to Tespa1 was also posttranslationally phosphorylated by intracellular Ca(2+) increase in HCT116 human colon cancer cells and HEK293 human embryonic kidney cells, suggesting that common signaling mechanism(s) may contribute to the molecular modification of Tespa1 and KRAP in different cellular processes. All these results suggested a novel molecular modification of Tespa1 and the existence of the regulatory pathway that SOCE affects the Tespa1-IP3R molecular complex.
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PMID:Tespa1 protein is phosphorylated in response to store-operated calcium entry. 2354 77

We describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles are coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulate T cells via the 4-1BB co-stimulatory pathway. These "immunoswitch" particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies. Immunoswitch particles enhance effector-target cell conjugation and bypass the requirement for a priori knowledge of tumor antigens. The use of the immunoswitch nanoparticles resulted in an increased density, specificity, and in vivo functionality of tumor-infiltrating CD8+ T cells. Changes in the T cell receptor repertoire against a single tumor antigen indicate immunoswitch particles expand an effective set of T cell clones. Our data show the potential of a signal-switching approach to cancer immunotherapy that simultaneously targets two stages of the cancer immunity cycle resulting in robust antitumor activity.
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PMID:Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth. 2858 25

Mucosal-associated invariant T (MAIT) cells all express a semi-invariable T cell receptor recognizing microbial metabolites presented on the MHC class I-like molecule MR1. Upon activation, they rapidly secrete cytokines and increase their cytotoxic potential. We showed recently that MAIT cells with Th1 phenotype accumulate in human colon adenocarcinomas. Here, we investigated the cytotoxic potential of tumor-infiltrating MAIT cells in colon adenocarcinomas, and to what extent it may be affected by the tumor microenvironment. Activation of MAIT cells from tumors induced increased Granzyme B, and to a lesser extent, perforin expression. Degranulation was assessed by surface expression of CD107a, and was also seen in response to cognate antigen recognition. The cytotoxic potential of tumor-associated MAIT cells was very similar to that of MAIT cells from unaffected colon. MAIT cells were also identified by immunofluorescence in direct contact with tumor cells in sections from colon cancer specimens. To summarize, tumor-associated MAIT cells from colon tumors have strong cytotoxic potential and are not compromised in this regard compared to MAIT cells from the unaffected colon. We conclude that MAIT cells may contribute significantly to the protective immune response to tumors, both by secretion of Th1-associated cytokines and by direct killing of tumor cells.
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PMID:Tumor-infiltrating mucosal-associated invariant T (MAIT) cells retain expression of cytotoxic effector molecules. 3107 72


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