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

doi:10.1016/j.celrep.2024.114333

DOT1L maintains NK cell phenotype and function for optimal tumor control

Cell Rep. 2024 Jun 25;43(6):114333. doi: 10.1016/j.celrep.2024.114333. Epub 2024 Jun 11.

Affiliations

¹ Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia.
² 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.
³ Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia; oNKo-Innate Pty Ltd, Moonee Ponds, VIC 3039, Australia.
⁴ Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁵ Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia; oNKo-Innate Pty Ltd, Moonee Ponds, VIC 3039, Australia. Electronic address: nicholas.huntington@monash.edu.
⁶ Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry, Monash University, Clayton, VIC 3800, Australia. Electronic address: sebastian.scheer@lih.lu.

PMID: 38865244
DOI: 10.1016/j.celrep.2024.114333

Abstract

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.

Keywords: CP: Cancer; CP: Immunology.

Publication types

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

MeSH terms

Animals
Histone-Lysine N-Methyltransferase* / genetics
Histone-Lysine N-Methyltransferase* / metabolism
Humans
Killer Cells, Natural* / immunology
Killer Cells, Natural* / metabolism
Mice
Mice, Inbred C57BL
Natural Cytotoxicity Triggering Receptor 1 / metabolism
Neoplasms* / immunology
Neoplasms* / pathology
Phenotype
Transforming Growth Factor beta / metabolism
Tumor Microenvironment / immunology

Substances

Dot1l protein, mouse
Histone-Lysine N-Methyltransferase
Natural Cytotoxicity Triggering Receptor 1
Transforming Growth Factor beta
DOT1L protein, human