T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?
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 alphaEbeta7-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 E-cadherin 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 51Cr-release 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 E-cadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function.
French
J J
JJ
Applied Immunobiology Group, Department of Surgery, The Medical School, University of Newcastle, NE2 4HH, UK.
Cresswell
J
J
Wong
W K
WK
Seymour
K
K
Charnley
R M
RM
Kirby
J A
JA
D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement / Q000502:physiology; D002857:Chromium / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D039001:Integrin alpha Chains / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism
D015703:Antigens, CD; D015820:Cadherins; D039001:Integrin alpha Chains; D016023:Integrins; D011948:Receptors, Antigen, T-Cell; C091367:alpha E integrins; C070709:integrin alphaEbeta7; D002857:Chromium