Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity

Abstract

Mucosal-associated invariant T (MAIT) cells belong to a family of innate-like T cells that bridge innate and adaptive immunities. Although MAIT cells have been implicated in tumor immunity, it currently remains unclear whether they function as tumor-promoting or inhibitory cells. Therefore, we herein used induced pluripotent stem cell (iPSC) technology to investigate this issue. Murine MAIT cells were reprogrammed into iPSCs and redifferentiated towards MAIT-like cells (m-reMAIT cells). m-reMAIT cells were activated by an agonist in the presence and absence of antigen-presenting cells and MR1-tetramer, a reagent to detect MAIT cells. This activation accompanied protein tyrosine phosphorylation and the production of T helper (Th)1, Th2, and Th17 cytokines and inflammatory chemokines. Upon adoptive transfer, m-reMAIT cells migrated to different organs with maturation in mice. Furthermore, m-reMAIT cells inhibited tumor growth in the lung metastasis model and prolonged mouse survival upon tumor inoculation through the NK cell-mediated reinforcement of cytolytic activity. Collectively, the present results demonstrated the utility and role of m-reMAIT cells in tumor immunity and provide insights into the function of MAIT cells in immunity.

Mice generated with induced pluripotent stem cells derived from mucosal-associated invariant T cells

“…MAIT cells are activated to produce cytokines such as IFN-γ and IL-17A in a TCR dependent and/or independent manner (Jesteadt et al, 2018, Leng et al, 2019, Rahimpour et al, 2015, Hinks and Zhang, 2020). Our recent study also found that redifferentiated MAIT cells from MAIT-iPSCs in vitro possessed similar properties (Sugimoto et al, 2022).…”

“…We previously established several iPSC clones derived from 5-OP-RU-loaded mouse MR1 tetramer (mMR1-tet) positive MAIT cells and confirmed that some clones possessed pluripotency through chimera formation (Sugimoto et al, 2022). Using the chimeric mice, we then attempted to generate novel C57BL/6 (B6) strains harboring rearranged TCR loci specific for MAIT cells.…”

“…Mice with 60∼90% chimerism were crossed with C57BL/6 females and resulting black-colored pups were screened for the presence of the rearranged configuration for Trav1-Traj33 and/or Trbv corresponding to the original iPSC clones (Figure S1). Among the chimeric mice, one line with 60-90% chimerism (#26 derived from iPSC clone L7-1 harboring Trav1-Traj33 and Trbv8-2-D1-J1-2 (Sugimoto et al, 2022)) successively gave rise to offspring bearing Trav1-Traj33, Trbv8-2-D1-J1-2 , or both (Table 1, Figure S1). Hereafter, these mouse strains are labeled Vα19 (harboring Trav1-Traj33 ), Vβ8 (harboring Trbv13-3-d1-j1-2 ), and Vα19/Vβ8 (harboring both Trav1-Traj33 and Trbv13-2-d1-j1-2 ), respectively.…”

“…Our previous study demonstrated that MAIT-like cells prepared from iPSCs exert anti-tumor activity, increasing mouse survival upon adoptive transfer (Sugimoto et al, 2022). Therefore, we explored whether the Vα19 and Vβ8 mice could exhibit a similar tumor resistance.…”

Enhancing Mucosal-Associated Invariant T (MAIT) cell function and expansion with human selective serum

“…10,19 and demonstration of anti-tumor effects in various mouse models of MAIT immunotherapy. 20,21 In humans, there is an increase in frequency of circulating CD4+ MAIT cells and a subsequent decrease of CD8+ MAIT cells compared to healthy controls suggesting that CD8+ T cells are infiltrating tumor sites. 22 Our MAIT cell expansion protocol was able to mitigate the increase of frequency of CD4+ MAIT cells, thus possibly offering improved anti-tumor activity over previously-published protocols for MAIT expansion, which resulted in an increased frequency of CD4+ MAIT cells.…”