DOT1L maintains NK cell phenotype and function for optimal tumor control
Harrison Sudholz,
Iona S. Schuster,
Momeneh Foroutan,
Xavier Sng,
Christopher E. Andoniou,
Anh Doan,
Tania Camilleri,
Zihan Shen,
Colby Zaph,
Mariapia A. Degli-Esposti,
Nicholas D. Huntington,
Sebastian Scheer
Affiliations
Harrison Sudholz
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia
Iona S. Schuster
Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia
Momeneh Foroutan
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia; oNKo-Innate Pty Ltd, Moonee Ponds, VIC 3039, Australia
Xavier Sng
Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Christopher E. Andoniou
Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia
Anh Doan
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia
Tania Camilleri
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia
Zihan Shen
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia
Colby Zaph
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia
Mariapia A. Degli-Esposti
Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia
Nicholas D. Huntington
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia; oNKo-Innate Pty Ltd, Moonee Ponds, VIC 3039, Australia; Corresponding author
Sebastian Scheer
Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia; Corresponding author
Summary: Histone methyltransferases (HMTs) are crucial in gene regulation and function, yet their role in natural killer (NK) cell biology within the tumor microenvironment (TME) remains largely unknown. We demonstrate that the HMT DOT1L limits NK cell conversion to CD49a+ CD49b+ intILC1, a subset that can be observed in the TME in response to stimulation with transforming growth factor (TGF)-β and is correlated with impaired tumor control. Deleting Dot1l in NKp46-expressing cells reveals its pivotal role in maintaining NK cell phenotype and function. Loss of DOT1L skews NK cells toward intILC1s even in the absence of TGF-β. Transcriptionally, DOT1L-null NK cells closely resemble intILC1s and ILC1s, correlating with altered NK cell responses and impaired solid tumor control. These findings deepen our understanding of NK cell biology and could inform approaches to prevent NK cell conversion to intILC1s in adoptive NK cell therapies for cancer.
