Background and aims: The prognosis of metastatic colorectal cancer is still poor, raising the need for alternative therapeutic approaches, particularly by manipulating the antitumour immune response. Advanced tumour stages, however, are frequently accompanied by functional T cell defects which may be critical for a T cell based anticancer immunotherapy. The aim of this study was to address whether T cells from colorectal cancer patients with advanced tumour stages can be specifically antigen activated against their autologous tumour cells.
Methods: T cells were isolated from colorectal cancer patients and retrovirally transduced to express a recombinant immunoreceptor that has an extracellular binding domain for carcinoembryonic antigen (CEA) and an intracellular CD3ζ signalling domain with and without CD28 costimulation for T cell activation.
Results: Peripheral blood T cells from colorectal cancer patients were successfully engineered to express the anti-CEA immunoreceptor on the cell surface. On coincubation with autologous CEA+ tumour cells, T cells with anti-CEA immunoreceptor are specifically activated to secrete interferon γ (IFN-γ) and to lyse autologous tumour cells whereas T cells without immunoreceptor are not. T cells equipped with combined CD3ζ-CD28 signalling receptor are more efficiently activated to secrete IFN-γ compared with T cells with CD3ζ signalling receptor. Induction of interleukin 2 secretion on targeting towards autologous tumour cells requires triggering of T cells by the CD3ζ-CD28 costimulatory receptor.
Conclusions: T cells from advanced colorectal cancer patients can be tumour specifically activated with high efficiency by engraftment with a combined CD3ζ-CD28 immunoreceptor to break tolerance against autologous tumour cells.
- CEA, carcinoembryonic antigen
- scFv, single chain antibody fragment
- mAb, monoclonal antibody
- TCR, T cell receptor
- XTT, 2,3-bis(2-methoxy-4-nitro-5sulphonyl)-5[(phenyl-amino)carbonyl]-2H-tetrazolium hydroxide
- FCS, fetal calf serum
- PE, phycoerythrin
- IFN-γ, interferon γ
- IL, interleukin
- recombinant T cell receptor
- CD28 costimulation
- carcinoembryonic antigen
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