Decreased expression of CD28 coincides with the down‐modulation of CD3ζ and augmentation of caspase‐3 activity in T cells from hepatocellular carcinoma‐bearing patients and hepatitis C virus‐infected patients

Maki, Akira; Matsuda, Masanori; Asakawa, Masami; Kono, Hiroshi; Fujii, Hideki; Matsumoto, Yoshirô

doi:10.1111/j.1440-1746.2004.03455.x

Cited by 22 publications

(18 citation statements)

References 33 publications

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“…Alternatively, removal of the tumor could have caused an abrogation of the TIS process. Our current model of TIS-T cells may explain how patients with cancer can have increases in both apoptotic and senescent T-cell phenotypes in the same peripheral blood lymphocytes (39). We confirmed the TIS process through other assays, such as lack of proliferation, expression of senescence-associated molecules, and telomere shortening.…”

Section: Discussionsupporting

confidence: 70%

Tumor-Induced Senescent T Cells with Suppressor Function: A Potential Form of Tumor Immune Evasion

Montes¹,

Chapoval²,

Nelson³

et al. 2008

Cancer Research

103

129

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Senescent and suppressor T cells are reported to be increased in select patients with cancer and are poor prognostic indicators. Based on the association of these T cells and poor outcomes, we hypothesized that tumors induce senescence in T cells, which negatively effects antitumor immunity. In this report, we show that human T cells from healthy donors incubated with tumor for only 6 h at a low tumor to T-cell ratio undergo a senescence-like phenotype, characterized by the loss of CD27 and CD28 expression and telomere shortening. Tumor-induced senescence of T cells is induced by soluble factors and triggers increases in expression of senescence-associated molecules such as p53, p21, and p16. Importantly, these T cells are not only phenotypically altered, but also functionally altered as they can suppress the proliferation of responder T cells. This suppression requires cell-to-cell contact and is mediated by senescent CD4 + and CD8 + subpopulations, which are distinct from classically described natural T regulatory cells. Our observations support the novel concept that tumor can induce senescent T cells with suppressor function and may effect both the diagnosis and treatment of cancer. [Cancer Res 2008;68(3):870-9]

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Section: Discussionsupporting

confidence: 70%

Tumor-Induced Senescent T Cells with Suppressor Function: A Potential Form of Tumor Immune Evasion

Montes¹,

Chapoval²,

Nelson³

et al. 2008

Cancer Research

103

129

View full text Add to dashboard Cite

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“…11,12 Circumstantial evidence for a physiological involvement of active caspase-3 in generating a CD3-f-chain-deficient T-cell phenotype has been described in patients with gastric and liver cancers. 13,14 T and B cells from Casp3 À/À mice show hyperproliferative responses, which have been attributed to reduced activation-induced cell death and to alterations of cell cycle regulation 15,16 in these cells, respectively. Caspase-3 also regulates many non-apoptotic cellular processes, such as cell proliferation, cell-cycle regulation and cell differentiation.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T‐cell receptor CD3‐ζ chain down‐regulation via caspase‐3 activation in oral cancer

et al. 2015

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SummaryDecreased expression of CD3-f chain, an adaptor protein associated with T-cell signalling, is well documented in patients with oral cancer, but the mechanistic justifications are fragmentary. Previous studies in patients with oral cancer have shown that decreased expression of CD3-f chain was associated with decreased responsiveness of T cells. Tumours are known to induce localized as well as systemic immune suppression. This study provides evidence that oral tumour-derived factors promote immune suppression by down-regulating CD3-f chain expression. 2 0 5 0 -Oligoadenylate synthetase 2 (OAS2) was identified by the proteomic approach and our results established a causative link between CD3-f chain down-regulation and OAS2 stimulation. The surrogate situation was established by over-expressing OAS2 in a HEK293 cell line and cell-free supernatant was collected. These supernatants when incubated with T cells resulted in down-regulation of CD3-f chain, which shows that the secreted OAS2 is capable of regulating CD3-f chain expression. Incubation of T cells with cell-free supernatants of oral tumours or recombinant human OAS2 (rh-OAS2) induced caspase-3 activation, which resulted in CD3-f chain down-regulation. Caspase-3 inhibition/down-regulation using pharmacological inhibitor or small interfering RNA restored down-regulated CD3-f chain expression in T cells induced by cell-free tumour supernatant or rh-OAS2. Collectively these results show that OAS2 leads to impairment in CD3-f chain expression, so offering an explanation that might be applicable to the CD3-f chain deficiency observed in cancer and diverse disease conditions.

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“…Interestingly, upregulation of PD-1 on TILs has been shown in HCC where the increased PD-1 expression correlates with an increased activity of caspase-3 and a decreased expression of CD3ζ and CD28 on CD8 + T cells. CD3ζ and CD28 are important for CD8 + T-cell activation and active caspase initiates apoptosis [62,63]. Indeed, in HCC, Kupffer cells, MDSCs, and tumor cells themselves can upregulate programmed cell death ligand-1 (PD-L1) and contribute thus to a decreased effector function of PD-1 expressing TAA-specific CD8 + T cells [64,65].…”

Section: Mechanisms Of Immune Suppressionmentioning

confidence: 99%

Cellular Immune Responses to Hepatocellular Carcinoma: Lessons for Immunotherapy

Schmidt

Neumann‐Haefelin

Thimme³

2012

Dig Dis

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Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a continuously high mortality. Thus, the development of new therapeutic strategies is crucial to decrease recurrence rates and to improve the overall survival rates of HCC patients. The rationale for immunotherapy is based on the findings of several studies showing specific CD8⁺ T-cell responses against various tumor-associated antigens (TAAs) in HCC patients and a clinical benefit of T-cell infiltration in the tumor tissue. However, the impact of TAA-specific CD8⁺ T-cell responses on tumor control seems to be rather weak. Several different mechanisms contribute to the failure of the cellular immune response and will be summarized in this review. The aim of immune-based therapies is to overcome these mechanisms of T-cell failure and to induce or boost TAA-specific CD8⁺ and CD4⁺ T-cell responses. Several preclinical and clinical studies of immune-based therapeutic approaches show encouraging results and will be discussed in this review.

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Decreased expression of CD28 coincides with the down‐modulation of CD3ζ and augmentation of caspase‐3 activity in T cells from hepatocellular carcinoma‐bearing patients and hepatitis C virus‐infected patients

Cited by 22 publications

References 33 publications

Tumor-Induced Senescent T Cells with Suppressor Function: A Potential Form of Tumor Immune Evasion

Tumor-Induced Senescent T Cells with Suppressor Function: A Potential Form of Tumor Immune Evasion

Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T‐cell receptor CD3‐ζ chain down‐regulation via caspase‐3 activation in oral cancer

Cellular Immune Responses to Hepatocellular Carcinoma: Lessons for Immunotherapy

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