Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
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Raw exome sequence data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EMBL-EBI) and the Centre for Genomic Regulation (CRG), under accession number EGAS00001002765.
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This work was funded in part by the Foundation of Stars. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the Fonds de la Recherche du Québec en Santé. D.-A.K.-Q. is a Herman Clinical Fellow. We thank N. Brousse and the Groupe Français d’Etude des Lymphomes Cutanés for their valuable contributions. We also thank S. Lade from the Peter MacCallum Cancer Centre and the Victorian Comprehensive Cancer Centre, Melbourne; P. McKelvie from the Department of Pathology at St. Vincent’s Hospital Melbourne; D. MacGregor from the Department of Pathology at the Royal Children’s Hospital (RCH) Melbourne; L. Dalla-Pozza from the Cancer Center for Children at The Children’s Hospital at Westmead, Sydney; C. Picard from the Study Center of Immunodeficiencies (CEDI) at Hôpital-Necker Enfants Malades, Paris; and G. Ménasché from INSERM U1163 at Institut Imagine, Paris. The Children’s Cancer Centre Tissue Bank at RCH Melbourne runs thanks to the generous support of Cancer in Kids @ RCH, Leukaemia Auxiliary at RCH, the Murdoch Children’s Research Institute, and the RCH Foundation. The Tumour Bank at the Children’s Hospital at Westmead is generously supported by the Kids Cancer Project. W.D.F. is funded by the Canadian Institute for Health Research (FDN-148390). The G.d.S.B. lab (INSERM 1163 at Institut Imagine) is Equipe labélisée Fondation pour la Recherche Médicale (FRM: DEQ20150734354) and is supported by l’Agence Nationale de la Recherche (ANR-12-BSV1-0020-01 and the Investissements d’Avenir program) and by the Fondation Imagine. A.F. is supported by Collège de France. T.G. and J.P. are recipients of Canadian Institutes of Health Research and Fonds de Recherche du Québec postdoctoral fellowships, respectively. A.B. is a recipient of a Fonds de Recherche du Québec doctoral studentship. E.T.V. was granted funding by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, grant no. 2015/20142-0/Brazil), as part of a research fellowship abroad program to participate in this project. We thank M. Fu and S.-B. Feng of the Molecular Imaging facility at the Research Institute of the McGill University Health Centre for their assistance with the confocal microscope.
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Nature Genetics (2018)