Two Heads Are Better Than One: The Combination of Dendritic Cells & B Cells Yields An Improved T Cell Response Over Dendritic Cells Alone When Presenting Tumour Lysate Antigens

Cancer;immunotherapy;dendritic cells;macrophages;B cells;tumour lysate;antigen presenting cells

Grant, Melanie LeVonne ; Young, Sarah L. ; Jackson, Christopher

University of Otago

关键词: Cancer;    immunotherapy;    dendritic cells;    macrophages;    B cells;    tumour lysate;    antigen presenting cells;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/6901/12/GrantMelanieL2016PhD.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

BACKGROUNDThe best APC for tumour immunotherapy is yet to be defined. The dendritic cell (DC) is well established as the key professional antigen-presenting cell (APC) for priming naïve T cells against tumours and for this reason it is the APC of choice in adoptive cell therapy (ACT) for cancer. However, robust clinical results with DC ACT remain disappointing and researchers are beginning to investigate the utility of alternative APCs, particularly B cells. DCs have been used as vaccines clinically to present tumour antigens in the form of tumour cell lysates, also with limited success. Tumour cell lysates represent an attractive source of tumour-associated antigens (TAAs) for cancer immunotherapy as their defined and undefined TAAs have the potential for simultaneous activation of CD4+ and CD8+ cytotoxic T lymphocytes (CTLs). Although their self-antigenic nature requires overcoming of inherent tolerance mechanisms as well as caution with regards to induction of autoimmunity.METHODSIn this study the ability of three professional APCs, DCs, macrophages (MΦs) and B cells, to stimulate an anti-tumour T cell response against tumour lysate (TL) antigens was compared. The activation profile and IL-12 response of the APCs to soluble freeze-thaw lysate (s-L) and oxidized whole freeze-thaw lysate (ox-L) was examined. Also investigated was the lysate-loaded APCs’ ability to induce T cell proliferation and effector functions, whether individually or in combination.RESULTSThe three APCs displayed differing responses to the two TLs indicative of differing T cell activation capacities. MHC-II and CD40 were upregulated on DCs in response to s-L and ox-L while MHC-II and CD86 were upregulated on B cells in response to s-L and ox-L. A synergistic increase in IL-12 production was observed in the lysate-loaded DC+B cell groups. No proliferation response was observed in lysate-primed CD4+ T cells. However, significant increases in CD8+ T cell proliferation were observed when T cells were primed with combinations of s-L-loaded APCs compared to a DC alone. The greatest proliferation was observed when CD8+ T cells were primed by the ox-L-loaded DC+B cell combination. The greatest IFN-γ levels were also observed in CD8+ T cells primed with lysate-loaded DC+B cells. The greatest in vivo cytotoxicity was achieved by ox-L-primed CD8+ T cells activated by the DC+B cell combination.SIGNIFICANCEBoth DCs and B cells are currently being investigated as APCs in adoptive cell therapy for cancer. This study demonstrates that combining DCs and B cells yields an improved CD8+ T cell response in a pre-clinical model of melanoma. Given that, in vivo, DCs do not present TAA in isolation, these results suggest that a single APC approach may be unnecessarily limiting the potential of ex-vivo APC adoptive cell therapy.