Pancreatic cancer cells can evade immune surveillance via nonfunctional Fas (APO-1/CD95) receptors and aberrant expression of functional Fas ligand

Bernstorff, Wolfram von; Spanjaard, Remco A.; Chan, Allen; Lockhart, Diane C.; Sadanaga, Noriaki; Wood, Isabelle; Peiper, Matthias; Goedegebuure, Peter S.; Eberlein, Timothy J.

doi:10.1016/s0039-6060(99)70291-6

Cited by 92 publications

(55 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected (Moldenhauer et al, 1999) this treatment led to HLA-DR surface expression (data not shown). In accordance with published data (Bernstorff et al, 1999), CD95 was constitutively expressed at the mRNA and protein level. After IFN␥ treatment there was no significant change in either CD95 mRNA or protein expression.…”

supporting

confidence: 89%

See 1 more Smart Citation

Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

Hasel

Rau

Perner

et al. 2001

Laboratory Investigation

View full text Add to dashboard Cite

SUMMARY:Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4 ϩ Th1 cytotoxic T cells induce apoptosis of their targets via oligomerizing CD95 (APO-1/Fas) death receptors on target cells by their CD95 ligand (CD95L). We determined the expression of CD95 and CD95L in epithelia of normal and chronically inflamed pancreatic tissues. We applied RT-PCR and Western blotting for CD95L expression profiles, serial frozen section immunohistochemistry to detect CD95, CD95L, and HLA-DR molecules, CD3, CD4, CD11c, and S-100 protein (S100p). Normal pancreases and chronic pancreatitis contain CD95L message and protein. Immunohistochemistry revealed a mutually exclusive expression of CD95 and CD95L. Physiologically, acini were CD95 Ϫ /CD95L ϩ , ducts were CD95 Ϫ /CD95L Ϫ , and islets were CD95 Ϫ /CD95L ϩ . In areas of lymphohistiocytic infiltration, mainly consisting of CD3 ϩ CD4 ϩ T cells and CD11c ϩ , CD4 ϩ/Ϫ , S100p ϩ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR ϩ , acini CD95 ϩ /CD95L Ϫ , and ducts CD95 ϩ /CD95L Ϫ . Islet cells were CD95 Ϫ /CD95L ϩ in both conditions. IFN␥ levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p Ͻ 0.0003). In vitro, IFN␥ downmodulated CD95L message and protein in ASPC1 and BxPc3 pancreatic carcinoma cells. In conclusion, pancreatic epithelia differentially express CD95 and CD95L in a mutually exclusive manner. In chronic pancreatitis the CD95 Ϫ /CD95L ϩ status is conserved in islet cells even in the vicinity of lymphohistiocytic infiltrates, whereas it is lost in acini coexpressing HLA-DR. As a potential consequence, and possibly triggered by local release of IFN␥, CD4 ϩ Th1 cells may cognately interact with and successfully attack exocrine cells by triggering CD95 on their target without being killed by epithelial, CD95L-mediated, counterattack. (Lab Invest 2001, 81:317-326).C hronic pancreatitis is characterized by a progressive loss and fibrosis of exocrine parenchyma whereas the endocrine part of the organ remains structurally intact for a prolonged period of time (Bockman, 1997;Klöppel and Maillet, 1993;Sarles, 1991). The disease is often accompanied by duct ectasia and might be initiated by ductal obstruction or distortion (Klöppel and Maillet, 1993). Furthermore, foci of lymphohistiocytic infiltrates are commonly found and are also associated with regressing parenchyma (Bockman, 1997). These infiltrates were shown to contain activated cytotoxic T cells (Hunger et al, 1997), suggesting a role of the immune system in the pathogenesis of acinar atrophy and local scarring. Induction of HLA-DR molecules was observed in parenchymal areas affected by chronic pancreatitis (Bedossa et al, 1990;Jalleh et al, 1993) and transcripts for MCP-1 chemokine have been detected in areas of early stage of chronic pancreatitis (Saurer et al, 2000). Local expression of T cell tropic chemokines may recruit T cell...

show abstract

supporting

confidence: 89%

“…1, A, B, D, and E). The pancreatic cell line AsPc1, known to express CD95L transcripts (Bernstorff et al, 1999;Ungefroren et al, 1998), was used as the positive control. The colon carcinoma cell line HT29 chosen as the negative control (O'Connell et al, 1996) did not reveal detectable amounts of CD95L message.…”

mentioning

confidence: 99%

Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

Hasel

Rau

Perner

et al. 2001

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…57-59 These cells express Fas, but depending to authors, are sensitive [47][48][49] or resistant 50,51 to Fas-mediated apoptosis. We show that Capan-1 cells regularly maintained in monolayer cultures, strongly express cytoplasmic and membrane-Fas and are sensitive to Fas-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…47,48,70,71 This may be an additional factor favoring the tumor formation, allowing tumor cells to survive and to counter-attack immune system cells. It has been shown that some tumor cell lines or specimens of primary tumors that express FasL, can induce apoptosis in Jurkat T cells 16,47,70,[72][73][74][75] or in activated T lymphocytes. 18,76 It would be interesting to follow and evaluate the expression of FasL as well as that of Fas in Capan-1 cell line and in xenografts.…”

Section: Discussionmentioning

confidence: 99%

“…There are some discrepancies in the observations of Fas functionality. Some authors describe these cells as being sensitive, [47][48][49] whereas others have found them to be resistant to Fas-mediated apoptosis. 50,51 Given the apparent significance of the environment in the expression of Fas in pancreatic cancerous cells, we examined Fas expression and function in the Capan-1 cell line, maintained successively in vitro and in vivo.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Serial in vivo loss and in vitro gain of Fas expression and function in human cancerous pancreatic duct cells

Radfar

Davrinche

Hollande

2005

Intl Journal of Cancer

View full text Add to dashboard Cite

Recent studies have shown the involvement of the Fas system (Fas receptor and its ligand FasL) in cancerous processes. The absence or downregulation of Fas, reported in the majority of human tumors, conflicts with its presence in cancerous cells from the same tumors but maintained in vitro. Recently, the eventual role of environmental factors in the loss of Fas expression, or in the in vivo selection of a Fas-negative cell population has been suggested. We determined the Fas expression and function in the Capan-1 human cancerous pancreatic duct cells over 2 successive passages in vivo separated by a period of 10-20 passages in vitro. We showed that Capan-1 cells express Fas and are sensitive to Fas-mediated apoptosis when maintained in vitro. When these cells were xenografted into nude mice the expression of Fas was lost in the majority of the tumors. Culture of tumor-derived cells exhibited that they became Fas-positive and sensitive to Fas-mediated apoptosis after a short period in vitro. The loss/gain of Fas was reproduced after re-explantation and re-culture of these Fasexpressing cells. Key words: Fas; Fas-mediated apoptosis; human pancreatic cancer; cell culture; xenograft The Fas/FasL system constitutes one of the main systems mediating the cytotoxicity of T cells and regulating immune responses, tissue development and homeostasis. 1 FasL and its receptor Fas (APO-1, CD95) are members of the tumor necrosis factor and tumor necrosis factor receptor family, respectively. Activation of Fas by its ligand 2 or by an agonistic antibody 3 induces programmed cell death (apoptosis) in functional Fas-bearing cells through a distinct cytoplasmic motif called 'Death Domain' (DD), 4,5 which interacts with FADD. 6,7 The recruitment of FADD allows the connection of the Fas receptor to cysteine proteases (Caspases) via FLICE. 8,9 Fas and FasL are highly expressed in activated T lymphocytes and natural killer cells. 1 However, these proteins are also constitutively expressed in many non-lymphoid tissues including several epithelial cell types. 10,11 Malignant cells possess several strategies to evade immune surveillance such as (i) low level expression of target antigens recognized by cytotoxic T lymphocytes, 12 (ii) decrease or loss of HLA (human leukocyte antigen) Class I or Class II molecule expression, which is required for antigen presentation 13,14 and (iii) suppression of immune cell function by secreting factors such as transforming growth factor-b. 15 Interestingly, tumor cells have developed another strategy (the Fas-counter-attack), 16 whereby loss of Fas expression or function and aberrant expression of FasL by tumor cells may contribute to the evasion of host immune surveillance by triggering apoptosis of tumor-specific T lymphocytes. 17,18 The loss or downregulation of Fas expression leading to Fasmediated apoptosis resistance has been reported in a variety of malignancies including cancers from: lung, 19,20 colon, 21 Human pancreatic cancer is the fourth (male) and fifth (female) leading cause of cancer de...

show abstract

Fas (CD95/APO‐1) and Fas ligand expression in normal pancreas and pancreatic tumors

Bernstorff

Glickman

Odze

et al. 2002

Cancer

Self Cite

View full text Add to dashboard Cite

BACKGROUND Fas (CD95/APO‐1) and Fas ligand (FasL) play key roles in immunologic homeostasis and immune privilege and may regulate normal cell turnover. Earlier studies had suggested that FasL‐positive pancreatic carcinoma cell lines can induce apoptosis in T cells, thereby evading host immune surveillance. In the current study the authors have characterized the expression of Fas and FasL in the normal pancreas and in pancreatic neoplasia. METHODS Pancreatic resection specimens with ductal‐type adenocarcinoma or intraductal dysplasia (n = 41), nonductal pancreatic neoplasms (n = 5), and chronic pancreatitis (n = 4) were examined for Fas and FasL expression by immunohistochemistry. The results in invasive adenocarcinoma were compared to those for benign ducts and intraductal dysplasia, and correlated with clinicopathologic features of the tumors and with patient survival. RESULTS Fas was expressed in the normal pancreatic ducts and in intraductal dysplasia in a mixed membrane/cytoplasmic pattern. In all cases of invasive ductal‐type adenocarcinoma, membranous Fas could not be detected; cytoplasmic Fas staining was reduced or completely lost. Loss of Fas expression in pancreatic ductal‐type adenocarcinomas significantly correlated with poorer differentiation and extrapancreatic spread of the tumors and was associated with a shorter overall survival. FasL expression was present in the normal pancreatic ducts as well as in islet cells and was maintained in all pancreatic tumors. CONCLUSIONS These results implicate the Fas pathway in the regulation of physiologic cell turnover and immune privilege in the normal pancreas and indicate that loss of Fas expression is correlated with malignant transformation and biologic aggressiveness in pancreatic adenocarcinomas. This may represent a mechanism by which pancreatic tumor cells become resistant to apoptosis and escape immune surveillance in vivo. Cancer 2002;94:2552–60. © 2002 American Cancer Society. DOI 10.1002/cncr.10549

show abstract

Pancreatic cancer cells can evade immune surveillance via nonfunctional Fas (APO-1/CD95) receptors and aberrant expression of functional Fas ligand

Cited by 92 publications

References 37 publications

Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

Serial in vivo loss and in vitro gain of Fas expression and function in human cancerous pancreatic duct cells

Fas (CD95/APO‐1) and Fas ligand expression in normal pancreas and pancreatic tumors

Contact Info

Product

Resources

About