MAIT cells regulate NK cell-mediated tumor immunity

Emma V Petley; Hui-Fern Koay; Melissa A Henderson; Kevin Sek; Kirsten L Todd; Simon P Keam; Junyun Lai; Imran G House; Jasmine Li; Magnus Zethoven; Amanda X Y Chen; Amanda J Oliver; Jessica Michie; Andrew J Freeman; Lauren Giuffrida; Jack D Chan; Angela Pizzolla; Jeffrey Y W Mak; Timothy R McCulloch; Fernando Souza-Fonseca-Guimaraes; Conor J Kearney; Rosemary Millen; Robert G Ramsay; Nicholas D Huntington; James McCluskey; Jane Oliaro; David P Fairlie; Paul J Neeson; Dale I Godfrey; Paul A Beavis; Phillip K Darcy

doi:10.1038/s41467-021-25009-4

MAIT cells regulate NK cell-mediated tumor immunity

Nat Commun. 2021 Aug 6;12(1):4746. doi: 10.1038/s41467-021-25009-4.

Authors

Emma V Petley^{1

2}, Hui-Fern Koay^{3

4}, Melissa A Henderson^{1

2}, Kevin Sek^{1

2}, Kirsten L Todd^{1

2}, Simon P Keam^{1

2

5}, Junyun Lai^{1

2}, Imran G House^{1

2}, Jasmine Li^{1

2}, Magnus Zethoven^{2

6}, Amanda X Y Chen^{1

2}, Amanda J Oliver^{1

2}, Jessica Michie^{1

2}, Andrew J Freeman^{1

2}, Lauren Giuffrida^{1

2}, Jack D Chan^{1

2}, Angela Pizzolla^{1

2}, Jeffrey Y W Mak^{7

8}, Timothy R McCulloch⁹, Fernando Souza-Fonseca-Guimaraes⁹, Conor J Kearney^{1

2}, Rosemary Millen^{1

2}, Robert G Ramsay^{1

2}, Nicholas D Huntington^{10

11

12}, James McCluskey³, Jane Oliaro^{1

2

13}, David P Fairlie^{7

8}, Paul J Neeson^{1

2}, Dale I Godfrey^#^{14

15}, Paul A Beavis^#^{16

17

18}, Phillip K Darcy^#^{19

20

21

22}

Affiliations

¹ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
³ Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
⁴ Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia.
⁵ Tumour Suppression and Cancer Sex Disparity Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁶ Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁸ Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia.
⁹ University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.
¹⁰ Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
¹¹ Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
¹² Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
¹³ Department of Immunology, Monash University, Melbourne, VIC, Australia.
¹⁴ Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. [email protected].
¹⁵ Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia. [email protected].
¹⁶ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. [email protected].
¹⁷ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. [email protected].
¹⁸ Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. [email protected].
¹⁹ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. [email protected].
²⁰ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. [email protected].
²¹ Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia. [email protected].
²² Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. [email protected].

^# Contributed equally.

Abstract

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents
Cell Line, Tumor
Cytokines
Histocompatibility Antigens Class I / genetics
Humans
Immunity
Immunity, Cellular*
Killer Cells, Natural / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Minor Histocompatibility Antigens / genetics
Mucosal-Associated Invariant T Cells / immunology*
Neoplasm Metastasis
Neoplasms / immunology*
Neoplasms / pathology

Substances

Antineoplastic Agents
Cytokines
Histocompatibility Antigens Class I
Minor Histocompatibility Antigens
Mr1 protein, mouse

Grants and funding

R01 AI148407/AI/NIAID NIH HHS/United States