Fighting Liver Metastasis by Activating MAIT Cells

Mucosal-associated invariant T (MAIT) cells represent an abundant T-cell subset in humans, especially in the liver. They are monospecific, recognizing the MR1 molecule loaded with unstable derivatives of the riboflavin biosynthetic pathway produced by bacteria and yeasts, for example, 5-OP-RU. In the thymus, MAIT cells acquire a particular differentiation program enabling them to elicit type-1 (IFNγ secretion and cytotoxicity) and type-17/tissue repair (IL17, IL22, and amphiregulin production) effector functions. In mice, these two functions are fulfilled by different MAIT subsets, whereas human MAIT cells are homogeneous, mediating type-1 and type-17 effector functions. MAIT-cell exposure to IL12 and IL18 induces type-1 effector functions, whereas TCR triggering stimulates type-17 functions. These context-dependent effector functions may explain the discrepancies in the literature regarding the role of MAIT cells in cancer. In humans, although bacteria are found in several solid tumors (1), colon carcinoma is the only one in which preferential MAIT-cell accumulation has been observed, which could be related to intratumoral bacterial invasion. In mice, MAIT cells may have a protumoral role, as reduced tumor growth is observed in several models of transplantable tumors in the absence of MAIT cells (2). Thus, it is unclear how MAIT cells interact with tumors at steady state and whether these cells can be used for therapeutic purpose. Ruf and colleagues provide important new insight into these issues (3).

To assess the potential of MAIT cells to fight liver metastasis in mice, Ruf and colleagues systemically provide 5-OP-RU together with CpG to activate and increase the number of MAIT cells, an approach previously used intranasally (4). The 5-OP-RU and CpG combination expands the MAIT-cell population in the liver and lungs, and decreases the growth of tumor cells that had simultaneously been injected into the liver. Ex vivo analyses of liver MAIT cells show this treatment increases the IFNγ and granzyme secretion potential of these cells and decreases IL17 expression. This does not require MR1 expression on tumor cells, suggesting that the protective effect mediated by MAIT cells is indirect, possibly via effects on natural killer (NK) cells and CD8⁺ T cells, which were activated in the treated group. Anti–asialo-GM1 treatment prevents the beneficial effect of MAIT-cell activation, further suggesting the involvement of NK cells. Because IL17 is thought to be responsible for the protumoral effect of MAIT cells (2), the beneficial effect of the 5-OP-RU and CpG combination treatment may be related to the increase in MAIT-cell frequency, the increase in type-1 functions, and the inhibition of type-17 functions. The relative role of these parameters remains to be determined.

Ruf and colleagues use a mouse model to show that stimulating MAIT cells may be used to fight tumors, especially in the liver (3). MAIT cells represent an attractive therapeutic target because of their abundance and residency in tissues. The monospecificity of MAIT cells enables pharmacologic stimulation of the whole population with reduced risk of off-target effect. Because of the potential protumoral effect of MAIT cells, which may be related to their type-17 capacity, the context of TCR stimulation of MAIT cells is probably crucial. Ruf and colleagues combine CpG with 5-OP-RU. As CpG biases the response toward type-1, it would be interesting to test whether other TLR ligands would have a similar impact on the antitumor functions of MAIT cells. The work of Ruf and colleagues clearly identifies MAIT cells as a potential target for cancer immunotherapy. The translatability of these data to humans, however, remains to be assessed given the differences between human and murine MAIT-cell characteristics and the need to identify or synthesize stable MAIT agonists.

O. Lantz reports personal fees from Biomunex, grants from Biomunex, and other support from Mnemo Therapeutics outside the submitted work.