Impact of epigenetic inhibitors on the in vitro modulation of human CD8 t cells

• Grant number: 19/09366-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): June 01, 2019
• Effective date (End): July 31, 2020
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Tiago da Silva Medina
• Grantee: Dálete Lohannye dos Santos Barcelos
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

CD8 T cells respond quite well under a certain stimulus presented by a given target cell. This process is essential for antigenic elimination e reestablishment of the host homeostasis. In general, this phenomenon is extremely efficient against acute infections, where specific T cell clones are activated and then undergo proliferation, which culminates in antigenic elimination, T cell contraction and induction of immunological memory. However, antigenic persistence in chronic viral infections or tumours leads to constant T cell receptor (TCR) activation. Depending on the repetitiveness, duration and magnitude of the TCR activation, CD8 T cells can acquire an exhausted profile. An excessive and sustained TCR activation is intrinsically associated with the induction of T cell exhaustion, which polarizes functional CD8 T cells towards a functionally inefficient pattern that is unable to eliminate chronic viral infections or tumours. Thus, the characterization and identification of chemical compounds capable of positively modulating CD8 T cell responses are essential for the development of therapeutic strategies in complex scenarios such as cancers. In this study, we will evaluate the modulatory activity of epigenetic inhibitors over the functionality of human CD8 T cells. To support this hypothesis, we recently found that epigenetic inhibitors have a great impact on the mouse and human CD4 T cell functionality. Some epigenetic inhibitors favour the regulatory arm of the immune response, whereas other compounds favour a pro-inflammatory response, by inducing inflammatory mediators such as IFN-gamma and TNF-alpha. Therefore, we hypothesized that epigenetic inhibitors can also act as regulators of the human CD8 T cell response. We believe that the to-be-tested epigenetic inhibitors will greatly regulate the effector activities of human CD8 T cells and might be used as a therapeutical strategy for tumour control.