IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment

Julie Leca; Franҫois Lemonnier; Cem Meydan; Jonathan Foox; Samah El Ghamrasni; Diana-Laure Mboumba; Gordon S Duncan; Jerome Fortin; Takashi Sakamoto; Chantal Tobin; Kelsey Hodgson; Jillian Haight; Logan K Smith; Andrew J Elia; Daniel Butler; Thorsten Berger; Laurence de Leval; Christopher E Mason; Ari Melnick; Philippe Gaulard; Tak W Mak

doi:10.1016/j.ccell.2023.01.003

IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment

Cancer Cell. 2023 Feb 13;41(2):323-339.e10. doi: 10.1016/j.ccell.2023.01.003. Epub 2023 Feb 2.

Authors

Julie Leca¹, Franҫois Lemonnier², Cem Meydan³, Jonathan Foox³, Samah El Ghamrasni⁴, Diana-Laure Mboumba⁵, Gordon S Duncan⁴, Jerome Fortin⁴, Takashi Sakamoto⁶, Chantal Tobin⁴, Kelsey Hodgson⁴, Jillian Haight⁴, Logan K Smith⁴, Andrew J Elia⁴, Daniel Butler⁷, Thorsten Berger⁴, Laurence de Leval⁸, Christopher E Mason⁹, Ari Melnick¹⁰, Philippe Gaulard¹¹, Tak W Mak¹²

Affiliations

¹ University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada. Electronic address: julie.leca@uhnresearch.ca.
² University Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France; AP-HP, Lymphoid Malignancies Unit, Henri Mondor Hospital, 94010 Créteil, France.
³ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
⁴ University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
⁵ University Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
⁶ University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁷ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA.
⁸ Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital, Lausanne 1011, Switzerland; Lausanne University, Lausanne 1011, Switzerland.
⁹ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA.
¹⁰ Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
¹¹ University Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France; AP-HP, Pathology Department, Henri Mondor Hosital, 94010 Créteil, France.
¹² University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada; Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. Electronic address: tak.mak@uhnresearch.ca.

PMID: 36736318
DOI: 10.1016/j.ccell.2023.01.003

Abstract

Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma that originates from T follicular helper (Tfh) cells and exhibits a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL, but their contribution to tumorigenesis is poorly understood. We developed an AITL mouse model that is driven by Idh2 and Tet2 mutations. Malignant Tfh cells display aberrant transcriptomic and epigenetic programs that impair TCR signaling. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered cross-talk with germinal center B cells that promotes B cell clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. The plasma cell count and angiogenesis are also increased in the Idh2-mutated tumors, implying a major relationship between Idh2 mutation and the characteristic AITL TME. Our mouse model recapitulates several features of human IDH2-mutated AITL and provides a rationale for exploring therapeutic targeting of Tfh-TME cross-talk for AITL patients.

Keywords: Angioimmunoblastic T cell lymphoma; Idh2; T follicular helper cells; Tet2; cytokines; epigenetics; germinal center B cells; preclinical mouse model; therapeutic agents; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA-Binding Proteins / genetics
Dioxygenases* / genetics
Humans
Immunoblastic Lymphadenopathy* / genetics
Isocitrate Dehydrogenase / genetics
Lymphoma, T-Cell* / genetics
Mice
Mutation
T Follicular Helper Cells / pathology
T-Lymphocytes, Helper-Inducer
Tumor Microenvironment / genetics

Substances

Dioxygenases
DNA-Binding Proteins
Isocitrate Dehydrogenase
TET2 protein, human
Tet2 protein, mouse

Grants and funding

CIHR/Canada