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Title: Characterisation of immune checkpoints in Richter syndrome identifies LAG3 as a potential therapeutic target
Epworth Authors: Yannakou, Costas
Other Authors: Gould, Claire
Lickiss, Jennifer
Kankanige, Yamuna
Yenerni, Satwica
Lade, Stephen
Gandhi, Maher
Chin, Collin
Villa, Diego
Slack, Graham
Markham, John
Tam, Constantine
Nelson, Niles
Seymour, John
Dickinson, Michael
Neeson, Paul
Westerman, David
Blombery, Piers
Keywords: Richter syndrome (RS)
Aggressive lymphoma
Chronic lymphocytic leukaemi (CLL)
Conventional immunochemotherapy
Immune checkpoint blockade
B-cell malignancies
Immune checkpoint profile of RS
Gene expression profiling
NanoString Human Immunology
Immunohistochemistry (IHC)
Small lymphocytic lymphoma (SLL)
Diffuse large B-cell lymphoma (DLBCL)
LAG3 expression
Tumour microenvironment (TME)
nCounter Human Immunology panel
Mono- and combination therapy
Cancer Services Clinical Institute, Epworth HealthCare, Victoria, Australia
Issue Date: 7-Aug-2021
Publisher: Wiley-Blackwell
Citation: Br J Haematol, 195: 113-118.
Abstract: 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.
DOI: 10.1111/bjh.17789
ISSN: 0007-1048
Journal Title: British Journal of Haematology
Type: Journal Article
Affiliated Organisations: Pathology Department, Peter MacCallum Cancer Centre
University of Melbourne, Melbourne
Mater Research, University of Queensland
Haematology, Princess Alexandra Hospital, Brisbane
Epworth Health Care, Melbourne, Australia
Centre for Lymphoid Cancer and Division of Medical Oncology, BC Cancer
Centre for Lymphoid Cancer and Department of Pathology and Laboratory Medicine
BC Cancer, Vancouver, Canada
Walter and Eliza Hall Institute of Medical Research
Royal Melbourne Hospital
CancerImmunology Program, Peter MacCallumCancer Centre, Melbourne, Australia
Type of Clinical Study or Trial: Clinical Trial
Appears in Collections:Cancer Services

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