Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome
Authors: Khuong-Quang Dong-Anh , Gayden Tenzin , Sepulveda Fernando , Pratt Jonathan , Valera Elvis , Garrigue Alexandrine , Kelso Susan , Sicheri Frank , Mikael Leonie , Hamel Nancy , Bajic Andrea , Dali Rola , Dervovic Dzana , Schramek Daniel , Guerin Frederic , Taipale Mikko , Nikbakht Hamid , Majewski Jacek , Moshous Despina , Charlebois Janie , Abish Sharon , Bole-Feysot Christine , Nitschke Patrick , Bader-Meunier Brigitte , Mitchell David , Thieblemont Catherine , Battistella Maxime , Gravel Simon , Nguyen Van-Hung , Conyers Rachel , Diana Jean-Sebastien , McCormack Christopher , Prince H. Miles , Besnard Marianne , Blanche Stephane , Ekert Paul G , Fraitag Sylvie , Foulkes William D , Fischer Alain , Neven Benedicte , Michonneau David , de Saint Basile Genevieve , Jabado Nada 
Published: October 2019

Abstract
Introduction
Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene.
Methods
We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3.
Results
We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells.
Conclusion
Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences.

Disclosures
Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.