Petley et al. showed that mice lacking MAIT cells had increased antitumor activity, mediated by increased numbers of matured NK cells. High expression of a MAIT cell gene signature in human tumor samples was associated with a negative impact on outcomes of patients with high NK cell tumor infiltration. In the activated context, human MAIT cells stimulated NK cells derived from patient tumor samples. In control mice, NK cell activation and antitumor responses were boosted by i.v. injection of MAIT cells stimulated in vitro with free MAIT cell antigen or MAIT cell antigen-pulsed tumor cells, or by intranasal delivery of MAIT cell antigen.
Contributed by Paula Hochman
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.
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Au
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (2) Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Tumour Suppression and Cancer Sex Disparity Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (10) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (18) Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia. (19) University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia. (20) University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (22) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (23) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (24) Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia. Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia. (25) Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Department of Immunology, Monash University, Melbourne, VIC, Australia. (27) Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia. (28) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (29) Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. godfrey@unimelb.edu.au. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia. godfrey@unimelb.edu.au. (30) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. paul.beavis@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. paul.beavis@petermac.org. Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. paul.beavis@petermac.org. (31) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. phil.darcy@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. phil.darcy@petermac.org. Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia. phil.darcy@petermac.org. Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. phil.darcy@petermac.org.
