Dr Ed Roberts - Immune Priming and the Tumour Microenvironment

Introduction

Roberts 2023

Tumour immunotherapy, most notably checkpoint blockade therapy, has produced remarkable benefits for patients with cancers that previously had poor outcomes. Blockade of the T cell inhibitory checkpoint molecules CTLA-4 and PD-1 has led to dramatic remissions that have lasted more than a decade in many patients. However, these responses are unfortunately restricted to only a subset of patients. Our work broadly aims to understand how the immune response to cancer is generated so as to understand what may limit the quality or quantity of that response. In this way, we hope to find new means of augmenting the response to immunotherapy in a broader subset of patients.

To do this, we are focusing on how the T-cell-mediated immune response is initiated. T cell responses begin in the lymph node, where they are directed by signals received from the peripheral tissue, where the challenge occurs. During responses to viruses, numerous signals drive re-organisation of the lymph node and choreograph a highly regulated process by which appropriate T cell activation can occur. It has been observed that the tumour-draining lymph node is improperly activated, suggesting priming may be less efficient against the tumour. Indeed vaccination, which improves priming, can improve immunotherapeutic approaches in mice, suggesting this as a viable approach. As such, our aim is to determine how the periphery communicates with and educates the lymph node during an efficient immune response and how this is subverted in the tumour setting. Of particular interest to us is the role of different dendritic cell subsets in organising and directing efficient immune responses in the lymph node, and how these are manipulated by the tumour microenvironment. In this way, we aim to discover signals by which we can convert the lymph node microenvironment into a more effective site of immune priming to augment existing immunotherapeutic responses.

Lab Report

pdf Roberts Lab Report (95 KB)

Key Publications

Binnewies M, Mujal AM, Pollack JL, Combes AJ, Hardison EA, Barry KC, Tsui J, Ruhland MK, Kersten K, Abushawish MA, Spasic M, Giurintano JP, Chan V, Daud AI, Ha P, Ye CJ, Roberts EW, Krummel MF. Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4(+) T Cell Immunity. Cell. 2019; 177: 556-571.e16

Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature medicine. 2018; 24: 541-50.

Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, Kaisho T, Bogunovic D, Bhardwaj N, Krummel MF. Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer cell. 2016; 30: 324-36.