Combining dendritic cells and B cells for presentation of oxidised tumour antigens to CD8+ T cells. Issue 7 (7th July 2017)

• Record Type: Journal Article
• Authors: Grant, Melanie L; Shields, Nicholas; Neumann, Silke; Kramer, Katrin; Bonato, Andrea; Jackson, Christopher; Baird, Margaret A; Young, Sarah L
• Is Part Of: Clinical & translational immunology. Volume 6:Issue 7 (2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-07-07
• Subjects: Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1038/cti.2017.28
• Languages: English
• ISSNs: 2050-0068

Abstract

Abstract : The dendritic cell (DC) is the foremost antigen‐presenting cell (APC) for ex vivo expansion of tumour‐specific patient T cells. Despite marked responses in some patients following reinfusion of DC‐activated autologous or HLA‐matched donor T cells, overall response rates remain modest in solid tumours. Furthermore, most studies aim to generate immune responses against defined tumour‐associated antigens (TAA), however, meta‐analysis reveals that those approaches have less clinical success than those using whole tumour cells or their components. Tumour lysate (TL) is used as a source of tumour antigen in clinical trials and potentially represents the full range of TAAs in an undefined state. Little is known about how different APCs cooperate to present TL antigens. We examined the effect of oxidised whole‐cell lysate (ox‐L) versus soluble fraction freeze–thaw lysate (s‐L) on bone marrow‐derived DCs and macrophages, and magnetic bead‐isolated splenic B cells. The APCs were used individually, or in combination, to prime T cells. CD8 + T cells produced interferon (IFN)‐γ in response to both s‐L and ox‐L, but only proliferated in response to ox‐L. IFN‐γ production and proliferation was enhanced by priming with the DC+B cell combination. Compared to DC alone, a trend toward greater interleukin (IL)‐12 production was observed when DC+B cell were loaded with s‐L and ox‐L antigens. CD8 + T‐cell specific lysis in vivo was greatest in ox‐L‐primed groups and DC+B cell priming significantly increased in vivo cytotoxicity compared to DC alone. These improved T‐cell responses with two APCs and stressed cell lysate has implications for APC‐based adoptive cell therapies. Cancer therapy: Turning T‐cells against tumors: An improved approach to cell‐based immunotherapy may help patients mount a more potent counterattack against cancer. Clinical researchers have attempted to train patients' T‐cells to destroy tumors by combining them with other immune cells that present tumor‐specific antigens. Until now results have been disappointing, but researchers led by Sarah Young at New Zealand's University of Otago have potentially found a way to improve the effectiveness of this approach. Antigen‐presenting cells are targeted against cancer by exposing them to broken‐up tumor cells. Young's team found this targeting was more effective when the tumor cells were first exposed to chemical stress. The researchers also identified a combination of antigen‐presenting cells that promoted a more aggressive T‐cell response in a mouse melanoma model. Young and colleagues are now exploring whether their improved immunotherapy approach might benefit glioma patients.