MAIT cells regulate NK cell-mediated tumor immunity

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

doi:10.1038/s41467-021-25009-4

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.

Highlights

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear
We investigated the impact of MAIT cell activation on tumor metastasis by pulsing tumor cells with the MAIT cell antigen 5-OP-RU prior to intravenous inoculation (Fig. 2a). 5OP-RU pulsing significantly upregulated MR1 on B16F10 melanoma cells (Fig. 2b), suggesting the tumor cells were able to present the 5-OP-RU antigen on their surface in an MR1dependent manner
Our observations of MAIT cell-deficient mice being more resistant to B16F10 lung metastasis and subcutaneous tumor growth suggested that MAIT cells interfere with effective antitumor immunity

Summary

Introduction

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. We show that MAIT cell-deficient mice have enhanced NK celldependent 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. Prepulsing 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. A study in patients with hepatocellular carcinoma suggests that increased MAIT cell infiltration correlated with an improved prognosis[32] Such divergent observations have been observed across numerous studies[9], making it difficult to know whether MAIT cells play a positive or negative role in anti-tumor immunity. Devising novel strategies to enhance MAIT cell activation represents a potential therapy for cancer, those which originate in, or metastasize to, tissues with high levels of MAIT cells, such as the liver and lung

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Results

Conclusion