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

Abstract

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.

CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung

“…In vitro, CD103 + CD8 + T cells even surpass CD103 -cells in cytotoxic killing capacity. CD103 + T cells have been shown before to be very potent cytotoxic killers in a number of other settings (41)(42)(43)(44)(45)(46). Additionally, CD103 + CD8 + lung T cells are also strong Th1 cytokine producers.…”

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

“…We speculate that a E (CD103)b 7 -mediated retention of T cells within tumor tissue might promote PD-1 upregulation by exacerbating the phenomenon of chronic antigen stimulation. Given that CD103 þ TIL have been observed in a number of other epithelial cancers, including colon, lung, pancreatic, and bladder cancer (29,(34)(35)(36)(37), this same phenomenon may have relevance beyond ovarian cancer. Indeed, a recent report indicates that CD103 and PD-1 are coexpressed by CD8 TIL in non-small cell lung carcinoma (38).…”

Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention

“…a E (CD103)h 7 integrin is expressed on a large proportion of CD8 + T cells infiltrating epithelial tumors (12,26,27). It has been assumed that CD103 may serve to locate T cells in epithelial tissues by engaging E-cadherin.…”