The Roles of CD4+ T cells and Regulatory T cells in Antitumour Immunity

Abstract

Although the immune system is rapidly becoming a key target for cancer treatment we still lack a comprehensive understanding of how the immune system affects cancer progression. Animal models, such as the one used in this thesis, help to delineate the complex feedback interactions between the immune system and cancer and to identify novel cellular and molecular targets for anticancer drugs. The negative role of regulatory T cells (Tregs) in cancer is well but their mechanism and cellular targets are not fully understood. This thesis uses a novel transgenic mouse model to establish how tumour-specific thymic Tregs (tTregs) and peripheral Tregs (pTregs) affect CD4+ T cell mediated tumour immunity and consequently altering the tumour microenvironment. Tumour-specific CD4+ T cells eradicated subcutaneous B16 melanoma despite a lack of direct interaction with tumour cells due to MHCII mismatch. Tumour rejection was driven by IFNγ+TNFα+IL2+ Th1 cells and was associated with neutrophil influx into the tumour. In some animals tumours recurred in the context of reduced Th1 and early CD4+ T cell conversion into pTregs, yet pTreg depletion did not trigger tumour rejection. Thymic Tregs suppressed CD4+ T cell-mediated tumour rejection in an antigen-dependent manner by reducing Th1 expansion. The response was rescued if tTregs were depleted from hosts prior to CD4+ T cell priming. Analysis of the tumour microenvironment identified several subsets of antigen-presenting cells (APCs) capable of presenting tumour antigen to CD4+ T cells ex vivo. Three previously unappreciated distinct dendritic cell (DC) populations (CD11b+, CD103+ and CD103-) were characterised and shown to have superior antigen-presenting capacity. CD4+ T cell transfer led to upregulation of both costimulatory and inhibitory markers on tumour APCs, while tTregs suppressed DC costimulation. These findings reported advance our understanding of the complex immune feedback mechanisms that control cancer progression.