Abstract
Much effort has been made to try to understand the relationship between chemotherapeutic treatment of cancer and the immune system. Whereas much of that focus has been on the direct effect of chemotherapy drugs on immune cells and the release of antigens and danger signals by malignant cells killed by chemotherapy, the effect of chemotherapy on cells surviving treatment has often been overlooked. In the present study, tumour cell lines: A549 (lung), HCT116 (colon) and MCF-7 (breast), were treated with various concentrations of the chemotherapeutic drugs cyclophosphamide, gemcitabine (GEM) and oxaliplatin (OXP) for 24 hours in vitro. In line with other reports, GEM and OXP upregulated expression of the death receptor CD95 (fas) on live cells even at sub-cytotoxic concentrations. Further investigation revealed that the increase in CD95 in response to GEM sensitised the cells to fas ligand treatment, was associated with increased phosphorylation of stress activated protein kinase/c-Jun N-terminal kinase and that other death receptors and activatory immune receptors were co-ordinately upregulated with CD95 in certain cell lines. The upregulation of death receptors and NKG2D ligands together on cells after chemotherapy suggest that although the cells have survived preliminary treatment with chemotherapy they may now be more susceptible to immune cell-mediated challenge. This re-enforces the idea that chemotherapy-immunotherapy combinations may be useful clinically and has implications for the make-up and scheduling of such treatments.
Highlights
One way that chemotherapies can sensitise tumour cells to immune-mediated apoptosis is by modifying the interaction between CD95 (FAS/APO-1) and its cognate ligand, FasL (CD178, CD95)
Initiating apoptosis in tumour cells through methods involving the augmentation of CD95 signalling is a treatment avenue that has been explored, mostly unsuccessfully, for a number of years[10] but a large swathe of evidence exists suggesting that chemotherapies sensitise tumours to CD95/FasL killing[11,12] and CD95 has been
Other molecules associated with immune-sensitivity, such as TRAIL receptors (TRAILRs) and NKG2D ligands have been reportedly induced by chemotherapies in various cancer types[15,16]
Summary
One way that chemotherapies can sensitise tumour cells to immune-mediated apoptosis is by modifying the interaction between CD95 (FAS/APO-1) and its cognate ligand, FasL (CD178, CD95). Ligation of CD95 with FasL is an important factor in immune-mediated clearance of cancer as this underpins the apoptosis of diseased cells by cytotoxic effector cells, such as natural killer cells (NKs) and αβ or γδ T-cells Activation of these immune effectors causes upregulation of FasL on the plasma membrane, increasing their cytolytic potential and when FasL on an effector cell ligates with CD95 on the surface of a target cell, such as a tumour cell, it instigates formation of a death-induced signalling complex and initiation of the caspase proteolytic cascade. Shown to be upregulated upon cells after treatment with a number of chemotherapeutics including: doxorubicin, cisplatin, mitomycin C, 5-FU, dacarbazine and gemcitabine[13,14] This phenomenon is observed in numerous cancers and is thought to be dependent of functional wild-type p53, either increasing translation of the FAS gene or translocation of the protein to the plasma membrane. In-line with recent reports additional signs of immune sensitivity will be explored in terms of expression of death receptors and immune effector ligands
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