Enhancing Adoptive Cell Transfer for the Treatment of Cancer

Adoptive;Cell;Transfer;ACT;T-cell;CD4;CD8;Dendritic;Macrophage;Tumour-antigen

Shields, Nicholas James ; Young, Sarah

University of Otago

关键词: Adoptive;    Cell;    Transfer;    ACT;    T-cell;    CD4;    CD8;    Dendritic;    Macrophage;    Tumour-antigen;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/5226/1/ShieldsNicholasJ2014BBiomedScHonours.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Cancer is currently the leading cause of death in New Zealand, accounting for 30% of all deaths in 2010.Due to factors such as an ageing population and poor lifestyle choices, the incidence and mortality of this disease is set to increase dramatically in the coming decades. This will exert substantial stress on the healthcare system, highlighting the urgent need for improved cancer therapies. The adoptive transfer of tumour-specific T lymphocytes, known as adoptive cell transfer (ACT), is a promising new approach to the treatment of cancer that has proven effective for the treatment of haematological malignancies and metastatic melanoma, achieving long-lasting clinical responses in approximately 50% of patients. The challenge now remains to enhance the therapeutic efficacy of ACT to enable a broad application of this therapeutic approach to the treatment of multiple types of cancer and achieve clinical responses in all patients.Using ovalbumin as a model tumour-antigen, the aim of this study was to (a), compare the ability of dendritic cells (DCs) and macrophages to generate tumour-specific CD4+ and CD8+ T cells for use in ACT, and (b), assess the phenotype and function of these generated cells. Splenocytes isolated from OT-I (CD8+) and OT-II (CD4+) transgenic mice were cultured with dendritic cells pulsed with respective ovalbumin peptide epitopes. After 10 days, these cells were restimulated with either dendritic cells or macrophages and cultured for a further 10 days. Macrophages could effectively generate tumour-specific CD8+ T cell responses but were poor inducers of CD4+ T cell responses compared to dendritic cells.In the case of CD8+ T cells, antigen-experienced T cells that were restimulated with macrophages exhibited superior phenotypic characteristics for use in ACT compared to DC-restimulated cells. Both DCs and macrophages predominately generated effector memory CD4+ T cells (CD44+CD62L-) and effector memory CD8+ T cells (CD44+CD62L-). Further phenotypic analysis of in vitro-generated T cells revealed distinct expression patterns of markers associated with T cell dysfunction, survival and differentiation. In response to their cognate antigen, generated T cells produced high levels of TNF-α and IFN-ɣ, suggesting that these cells can mediate effective tumour destruction in vivo.Future experiments will determine the length of time that adoptively transferred T cells persist in vivo and assess the efficacy of ACT using generated CD4+ and CD8+ T cells in an in vivo murine B16-OVA melanoma model.