Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+ CD18+ cells and CD8+ CD103+ cells by multi-epitope imaging

Ademmer, Karin; Ebert, Matthias P.; Müller-Ostermeyer, Frauke; Friess, Helmut; Büchler, Markus W.; Schubert, Walter; Malfertheiner, Peter

doi:10.1046/j.1365-2249.1998.00546.x

Cited by 64 publications

(58 citation statements)

References 33 publications

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“…The results from this model are consistent with previous studies (Austrup et al, 1995), although the methodology described in the current report is novel. Previous in vitro studies demonstrate that the majority of T cells of the CD103 phenotype are activated CD8+ cells (Cerf-Bensussan et al, 1987;Rihs et al, 1996;Ademmer et al, 1998;Fujihara et al, 1999). The population produced in vitro using the technique in the current study was essentially similar to IEL with regards to activation and predominance of the CD8 phenotype.…”

Section: Discussionmentioning

confidence: 98%

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

et al. 2002

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Pancreatic cancer is an aggressive and potent disease, which is largely resistant to conventional forms of treatment. However, the discovery of antigens associated with pancreatic cancer cells has recently suggested the possibility that immunotherapy might become a specific and effective therapeutic option. T cells within many epithelia, including those of the pancreas, are known to express the aEb7-integrin adhesion molecule, CD103. The only characterised ligand for CD103 is E-cadherin, an epithelial adhesion molecule which exhibits reduced expression in pancreatic cancer. In our study, CD103 was found to be expressed only by activated T cells following exposure to tumour necrosis factor beta 1, a factor produced by many cancer cells. Significantly, the expression of this integrin was restricted mainly to class I major histocompatibility complex-restricted CD8+ T cells. The human pancreatic cancer cell line Panc-1 was transfected with human E-cadherin in order to generate Ecadherin negative (wild type) and positive (transfected) sub-lines. Using a sensitive flow cytometric adhesion assay it was found that the expression of both CD103 (on T cells) and E-cadherin (on cancer cells) was essential for efficient adhesion of activated T cells to pancreatic cancer cells. This adhesion process was inhibited by the addition of antibodies specific for CD103, thereby demonstrating the importance of the CD103?E-cadherin interaction for T-cell adhesion. Using a 51 Crrelease cytotoxicity assay it was found that CD103 expressing T cells lysed E-cadherin expressing Panc-1 target cells following T cell receptor stimulation; addition of antibodies specific for CD103 significantly reduced this lysis. Furthermore, absence of either CD103 from the T cells or E-cadherin expression from the cancer cells resulted in a significant reduction in cancer cell lysis. Therefore, potentially antigenic pancreatic cancer cells could evade a local anti-cancer immune response in vivo as a consequence of their loss of E-cadherin expression; this phenotypic change may also favour metastasis by reducing homotypic adhesion between adjacent cancer cells. We conclude that effective immunotherapy is likely to require upregulation of Ecadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function.

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Section: Discussionmentioning

confidence: 98%

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

et al. 2002

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“…Evidences for involvement of adaptive immunity in pancreatic cancer are the presence of immune infiltrates at the tumor site consisting of memory CD4 ϩ and CD8 ϩ T cells (4,5) and of tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients (6 -10). However, mechanisms of immune evasion adopted by the tumor (11)(12)(13)(14)(15) as well as released factors and immune regulatory cells present at the tumor site possibly affect the efficacy of antitumor immunity in pancreatic cancer (16 -20).…”

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confidence: 99%

Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Tassi

Gavazzi

Albarello

et al. 2008

The Journal of Immunology

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Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients’ sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80–90% of pancreatic carcinomas and contains epitopes recognized by CD4+ T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the anti-CEA and antiviral CD4+ T cell immunity. CD4+ T cells from 23 normal donors and 44 patients undergoing surgical resection were tested for recognition of peptides corresponding to CEA and viral naturally processed promiscuous epitopes by proliferation and cytokine release assays. Anti-CEA CD4+ T cell immunity was present in a significantly higher number of normal donors than pancreatic cancer patients. Importantly, whereas CD4+ T cells from normal donors produced mainly GM-CSF and IFN-γ, CD4+ T cells from the patients produced mainly IL-5, demonstrating a skew toward a Th2 type. On the contrary, the extent of antiviral CD4+ T cell immunity was comparable between the two groups and showed a Th1 type. The immunohistochemical analysis of tumor-infiltrating lymphocytes showed a significantly higher number of GATA-3+ compared with T-bet+ lymphoid cells, supporting a Th2 skew also at the tumor site. Collectively, these results demonstrate that Th2-immune deviation in pancreatic cancer is not generalized but tumor related and suggests that the skew might be possibly due to factor(s) present at the tumor site.

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“…In addition, cytokines activate Notch, and Hedgehog signalling synergistically with KRas to accelerate PDAC development [30,95]. Myeloid derived suppressor cells (MDSCs), immunosuppressive cell type, suppress CTL response and induce development of regulatory T cells (Tregs) [84,91,92]. The majority of the T-lymphocytes in PDAC are Tregs, involved in suppression of the immune response, and significantly increased in the blood of PDAC patients as well as in the pancreatic tissue [92,93].…”

Section: Uchl1mentioning

confidence: 99%

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

Korhan¹,

Verkerk²,

Critchley³

2017

Integr Mol Med

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Pancreatic ductal adenocarcinoma (PDAC) arises from epithelia of pancreas. Despite its low incidence, it is the most lethal cancer type. Although the poor outcome is largely secondary to the high proportion of patients who are diagnosed with advanced disease, the prognosis of PDAC is also influenced by the inherent biological aggressiveness and the high metastatic potential of this malignancy. Treatment options remain limited with little progress over the last decades. Some improvements in surgical outcome occur in patients who also receive chemotherapy and/or radiotherapy, however, the impact on long-term survival has been minimal owing to the intense resistance of PDAC to all extent treatments regimen. Hence, there is an urgent need to 1) gain better understanding of the biology of PDAC; 2) to develop early detection and prevention programs; 3) to identify new therapeutic strategies to improve quality of life and survivorship. In this review, first, we will summarise the state of knowledge of PDAC pathogenesis with a particular the focus on the molecular characteristics causing therapeutic resistance. Then, we will briefly review current and emerging approaches in the PDAC care. Lastly, we will highlight the integrative approaches in the light of new experimental and clinical research conducted with the aim of moving towards personalised therapy in patients with PDAC.

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Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+ CD18+ cells and CD8+ CD103+ cells by multi-epitope imaging

Cited by 64 publications

References 33 publications

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

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