Title: Revealing anti-tumour T cell recruitment and recirculation in vivo to optimise therapeutic intervention
Funder: Cancer Research UK

Abstract: Background Lymph nodes (LNs) are hubs of the immune system, screening local tissues for signs of infection, damage or cancer. Thus tumour draining LNs are key sites where anti-tumour T cells are expanded, instructed and regulated. Our knowledge of the dynamic movement of T cells into and out of tumours is limited at present by technical challenges. To address this, we have established new in vivo models to precisely assess T cell migration from the tumour draining LN into the tumour, informing where T cells have been, where they have gone and when they changed. Aims The fundamental aim of this proposal is to assess the migration of T cells into tumours and determine how these cells change upon entry into this microenvironment. Also, we will determine whether circulating memory T cells are formed, which provide systemic protection against recurrent disease. Armed with this knowledge, we will determine the impact of novel therapies currently in clinical trials on anti-tumour T cell recruitment and recirculation. Methods 1. We will use photoconvertible mice grafted with syngeneic tumour cell lines to study the migration of anti-tumour T cells. We will assess two well-characterised tumour models that show different levels of T cell infiltration and enable the tracking of antigen-specific populations. We will analyse dynamic changes in expression of key molecules using flow cytometry. 2. Using the cell line models (in 1.) we will determine the effect of novel therapies designed to enhance the anti-tumour T cell response, in terms of T cell recruitment and the establishment of circulating memory cells. 3. We will determine the recruitment and recirculation of anti-tumour T cells in spontaneous tumours alongside therapeutic interventions (in 2.) to better model anti-tumour responses in patients. How the results of this research will be used? This research will provide novel insight into the dynamic changes that occur in T cells upon entry into the tumour environment, revealing key new information on the dynamics of inhibitory and costimulatory receptor expression. This will instruct the optimisation of current therapies and/or the design of new ones. We will determine the nature of the memory anti-tumour T cells and directly assess the ability of these cells to recirculate and provide systemic protection. Armed with this understanding, we will apply this knowledge to determining how different therapeutic approaches that target the tumour microenvironment actually impact on anti-tumour T cell recruitment and the establishment of systemic protection.

Lay abstract: Background Lymph nodes (LNs) are hubs of the immune system, screening local tissues for signs of infection, damage or cancer. Thus tumour draining LNs are key sites where anti-tumour T cells are expanded, instructed and regulated. Our knowledge of the dynamic movement of T cells into and out of tumours is limited at present by technical challenges. To address this, we have established new in vivo models to precisely assess T cell migration from the tumour draining LN into the tumour, informing where T cells have been, where they have gone and when they changed. Aims The fundamental aim of this proposal is to assess the migration of T cells into tumours and determine how these cells change upon entry into this microenvironment. Also, we will determine whether circulating memory T cells are formed, which provide systemic protection against recurrent disease. Armed with this knowledge, we will determine the impact of novel therapies currently in clinical trials on anti-tumour T cell recruitment and recirculation. Methods 1. We will use photoconvertible mice grafted with syngeneic tumour cell lines to study the migration of anti-tumour T cells. We will assess two well-characterised tumour models that show different levels of T cell infiltration and enable the tracking of antigen-specific populations. We will analyse dynamic changes in expression of key molecules using flow cytometry. 2. Using the cell line models (in 1.) we will determine the effect of novel therapies designed to enhance the anti-tumour T cell response, in terms of T cell recruitment and the establishment of circulating memory cells. 3. We will determine the recruitment and recirculation of anti-tumour T cells in spontaneous tumours alongside therapeutic interventions (in 2.) to better model anti-tumour responses in patients. How the results of this research will be used? This research will provide novel insight into the dynamic changes that occur in T cells upon entry into the tumour environment, revealing key new information on the dynamics of inhibitory and costimulatory receptor expression. This will instruct the optimisation of current therapies and/or the design of new ones. We will determine the nature of the memory anti-tumour T cells and directly assess the ability of these cells to recirculate and provide systemic protection. Armed with this understanding, we will apply this knowledge to determining how different therapeutic approaches that target the tumour microenvironment actually impact on anti-tumour T cell recruitment and the establishment of systemic protection.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS