Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Dickinson, Michael × Author: Seymour, John × Author: Westerman, David × End date: 2021 × Start date: 2020 ×

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    Characterisation of immune checkpoints in Richter syndrome identifies LAG3 as a potential therapeutic target
    Gould, C ; Lickiss, J ; Kankanige, Y ; Yemeni, S ; Lade, S ; Gandhi, MK ; Chin, C ; Yannakou, CK ; Villa, D ; Slack, GW ; Markham, JF ; Tam, CS ; Nelson, N ; Seymour, JF ; Dickinson, M ; Neeson, PJ ; Westerman, D ; Blombery, P (WILEY, 2021-10)
    Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.