Lymphocyte apoptosis induced by Fas ligand- expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes.

Rabinowich, Hannah; Reichert, Torsten E.; Kashii, Yoshiro; Gastman, Brian; Bell, Maria C.; Whiteside, Theresa L.

doi:10.1172/jci1518

Cited by 199 publications

(112 citation statements)

References 28 publications

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“…27 The mechanisms involved in tumor-induced downregulation of -chain expression in T cells are still not fully understood, but preliminary data indicate that direct contact with tumor or tumor-derived factors might initiate intracellular caspases in activated T cells, which participate in degradation of the -chain and perhaps other signaling molecules. 18,19 This interpretation fits well with the presence of normal levels of -chain mRNA present in PBL. It should be noted, however, that both patients received the alkylating chemotherapeutic agent temozolomide during the last part of the observation period.…”

Section: Discussionsupporting

confidence: 70%

“…However, it has been shown that the mRNA levels of the CD3 -chain may remain unaffected, whereas the protein level is decreased. 18,19 For this reason, the CD3 -chain protein level was examined by Western blotting. Data from these analyses clearly demonstrated a substan- tially decreased amount of CD3 -chain protein at time 6 compared to time 1 (Fig.…”

Section: Expression Of the Cd3 -Chain In Pbl And Til During The Coursmentioning

confidence: 99%

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Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression

et al. 2001

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Two HLA-A2-positive patients with advanced stage IV melanoma were treated with monocyte-derived dendritic cells (DC) pulsed with either tumor peptide antigens from gp100, MART-1 and MAGE-3 alone or in combination with autologous oncolysates. Clinically, the rapid progression of disease was substantially stalled and both patients were alive for more than 15 months after initiation of therapy. Specific CTL reactivity against several tumor antigens was detectable in peripheral blood, which declined just before reactivation of disease progression. Furthermore, CD3 -chain expression detected by Western blotting was decreased in PBL at this time. In summary, our data confirm that DC-based vaccinations induce peptide-specific T cells in the peripheral blood of advanced-stage melanoma patients. Although successful induction of systemic tumor antigen-specific CTL may not lead to objective clinical tumor regression, their presence are indicative of a prolonged survival.

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Section: Discussionsupporting

confidence: 70%

Section: Expression Of the Cd3 -Chain In Pbl And Til During The Coursmentioning

confidence: 99%

Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression

et al. 2001

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“…While patients' T cells may recover expression of z in part during ex vivo stimulation with anti-CD3 mAb, z remained low at 24 or 48 h of culture relative to its expression in normal T cells incubated in parallel. Downregulation of z expression has been reported in T and NK cells of patients with cancers (Zea et al, 1995;Rabinowich et al, 1996Rabinowich et al, , 1998Reichert et al, 1998a, b;Kiessling et al, 1999;Kuss et al, 1999;Whiteside, 1999Meidenbauer et al, 2002;Reichert et al, 2002) and with chronic infections, including HIV (Stefanova et al, 1996;Zea et al, 1998). A transient loss of z expression appears to be a normal consequence of signalling via TcR (Valiutti et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

“…Recent data from our laboratory and other laboratories indicate that tumour-infiltrating and peripheral T cells of many patients with cancer are primed for apoptosis (Rabinowich et al, 1998;Reichert et al, 1998b;Lee et al, 1999;Reichert et al, 2002;, and that the death of effector T cells could be responsible for inadequate antitumour functions. We previously reported that relative to healthy normal controls (NC), patients with cancer have increased proportions of circulating T cells that bind Annexin V (Dworacki et al, 2001;Hoffmann et al, 2002).…”

mentioning

confidence: 89%

Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck

et al. 2003

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A subset of circulating T cells (CD8 + CD45RO À CD27 À ) with a naïve phenotype, but mediating effector function, is considered to play an important role in host antitumour defence. To investigate the attributes of these effector T cells in patients with squamous cell carcinoma (SCC) of the head and neck cancer, venous blood was obtained from 39 individuals with cancer and 45 normal controls (NC). Peripheral blood mononuclear cells were isolated, stained with labelled monoclonal antibodies specific for CD8, CD45RO, CD45RA, CD62L, CD27, TCR-z as well as isotype controls and examined by multicolour flow cytometry. Annexin V binding to CD8 + T cells and PMA/ionomycin-induced IFN-g expression were also evaluated in patients and NC. The proportions of CD45RA + CD45RO À (naïve) and CD45RA À CD45RO + (memory) cells were found to be comparable within the CD8 + T-cell subset. However, relative to NC, the frequency of effector CD8 + CD45RO À CD27 À cells was strikingly increased in all SCC patients regardless of the disease status (P ¼ 0.0003). The proportion of these cells was found to increase with age in both patients and NC. In NC, stimulated IFN-g expression was largely restricted to CD8 + CD45RO À CD27 + cells, while in patients CD8 + CD45RO À CD27 À expressed IFN-g after ex vivo stimulation. Expression of the TCR-associated z chain was decreased or absent in freshly isolated CD8 + CD45RO À CD27 À T cells in patients (Po0.0001). Annexin V was found to bind to a higher proportion of circulating CD8 + T cells in patients than NC (Po0.006), and significantly more Annexin V + T cells were present in the effector (Po0.0059) than the naïve subset within the CD8 + CD45RO À compartment. The data indicate that the expanded CD8 + CD45RO À CD27 À T cells, which contain precursors of IFN-g-producing T cells, are z-negative and sensitive to apoptosis in the circulation of patients with HNC.

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“…'Exosomes' from four out of six patients were positive for the presence of B23 by Western immunoblots ( Figure 3C). Since other investigators have suggested the antitumour cellular immune response can be suppressed by the presence of Fas ligand (FasL) (Rabinowich et al, 1998;Whiteside, 2002), shed 'exosomes' were assessed for expression of FasL. All 225 000 P a t i e n t 1 P a t i e n t 2 P a t i e n t 3 P a t i e n t 4 P a t i e n t 5 samples were positive for the intact 41 kDa form of FasL and two were also strongly positive for the 27 kDa cleaved form ( Figure 3B).…”

Section: Characterisation Of Antigens Associated With Membrane Vesiclesmentioning

confidence: 99%

Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects

2005

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Dendritic and lymphoid 'exosomes' regulate immune activation. Tumours release membranous material mimicking these 'exosomes,' resulting in deletion of reactive lymphocytes. Tumour-derived 'exosomes' have recently been explored as vaccines, without analysis of their immunologic consequences. This investigation examines the composition of tumour-derived 'exosomes' and their effects on T lymphocytes. Membranous materials were isolated from ascites of ovarian cancer patients (n ¼ 6) and Western immunoblotting was performed for markers associated with 'exosomes.' Using cultured T cells, 'exosomes' were evaluated for suppression of CD3-z and JAK 3 expressions and induction of apoptosis, measured by DNA fragmentation. 'Exosome' components mediating suppression of CD3-z were isolated by continuous eluting electrophoresis and examined by Western immunoblotting. 'Exosomes' were shown to be identical with previously characterised shed membrane vesicles by protein staining and TSG101 expression. 'Exosomes' expressed class I MHC, placental alkaline phosphatase, B23/nucleophosmin, and FasL. 'Exosomes' suppressed expression of T-cell activation signalling components, CD3-z and JAK 3 and induced apoptosis. CD3-z suppression was mediated by two components: 26 and 42 kDa. Only the 42 kDa component reacted with anti-FasL antibody. These results indicate that, while 'exosomes' express tumour antigens, leading to their proposed utility as tumour vaccines, they also can suppress T-cell signalling molecules and induce apoptosis.

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Lymphocyte apoptosis induced by Fas ligand- expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes.

Abstract: Abstract

Cited by 199 publications

References 28 publications

Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression

Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression

Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck

Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects

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