Does lymphoma avoid immune destruction by inducing T-cell tolerance? (2016–2017)
Abstract:
Lymphoma is the most common haematological malignancy in Australia and the sixth most common cancer overall. In 2007, 4600 new cases were diagnosed and 1,389 deaths were due to lymphoma in Australia. Unfortunately, incidence is increasing and has doubled over the past two decades. Despite advances in treatment, disease is incurable in around 30% of cases. We propose that unique aspects of B-cell function, namely their capacity to inactivate antigen-specific CD8+ T cells, imparts B lymphomas with the capacity to potently disable anti-tumour responses. This may underlie the ability of B lymphomas to escape immune recognition and be a critical factor limiting their resolution. EBV is strongly associated with several subtypes of B-lymphoma including EBV+ve Diffuse Large B-Cell Lymphoma (DLBCL) of the elderly. Importantly for our studies, EBV proteins act as tumour antigens that allow tumour-specific T-cell responses to be tracked. We will take advantage of this and use a combination of techniques to assess whether tumour-specific T-cells are 'turned-off' as a consequence of B-lymphoma development. AIM 1: Define the phenotypic characteristics of lymphoma-specific T cells. The frequency and phenotype of EBV-specific (i.e. tumour-specific) T-cells and non-tumour specificities will be compared between EBV+ve DLBCL patients and healthy controls. AIM 2: Determine the functional capacity of lymphoma-specific T cells. The function of EBV-specific and non-tumour specificities in EBV+ DLBCL patients and controls will be compared. AIM 3: Define the transcriptional profile of human lymphoma¿¿¿specific T cells. We will use transcriptional profiling of tumour-specific and non-specific CD8+ T cells to define transcriptional signatures and gene networks in T cells from Aims 1 & 2. The studies will provide critical understanding that will guide how conventional and immune-therapy of lymphoma, and possibly other ...
