Abstract
Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients. Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. Moreover, immunomodulatory drugs Lenalidomide and Pomalidomide, indirectly inhibited MAIT cell activation. We further show that cell lines can be pulsed with vitamin-B derivative Ags and that these can be presented via MR1 to MAIT cells in vitro, to induce cytotoxic activity comparable to that of natural killer (NK) cells. Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.
Highlights
Multiple myeloma is a haematological malignancy characterised by a clonal outgrowth of malignant plasma cells in the bone marrow[1]
Using MHC-related protein 1 (MR1)–5-OP-RU tetramers[17] in combination with an antibody directed against TRAV1-2+ TCRs, Mucosal-associated invariant T (MAIT) cells were identified via flow cytometry (Fig. 1A) which allowed their enumeration in peripheral blood (PB)
MAIT cells are capable of recognising microbial metabolites as Ags, including the potent Ag 5-OP-RU, presented by MR120
Summary
Multiple myeloma is a haematological malignancy characterised by a clonal outgrowth of malignant plasma cells in the bone marrow[1]. Whereas conventional peptide-MHC-reactive T cells are the main focus of many studies into cancer immunotherapy, there is growing interest in the potential to harness unconventional T cells that are not peptide-MHC reactive These studies include, for example, modulation of CD1d-lipid-antigen (Ag)-restricted type I NKT cells using the lipid-Ag α-galactosylceramide[9], and the phospho-Ag-reactive Vγ9Vδ2 γδ T cells using bisphosphonates such as zoledronic acid[10]. Compared to their peptide-MHC-restricted conventional T cell counterparts, the high precursor frequency, restriction to monomorphic antigen-presenting molecules, and powerful immunomodulatory properties give unconventional T cells great potential as a therapeutic target[11,12]. While MR1 can bind derivatives of both folate (vitamin B9) and riboflavin (vitamin B2), MAIT cells are universally and potently activated by the Ag 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a chemical metabolite formed as a byproduct of microbial biosynthesis of riboflavin through condensation of a biosynthetic intermediate with the glycolysis metabolite pyruvaldehyde[20]
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