Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity
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Evaluation Summary:
This paper describes a reprogramming platform for studying mucosal-associated invariant T (MAIT) cells that can overcome the current technology limitations in studying MAITs. With more detailed elucidation the identity of reprogrammed MAIT cells compared to endogenous MAITs, this paper will of broad interest to those studying the role of these cells in tumor immunity.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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.
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Evaluation Summary:
This paper describes a reprogramming platform for studying mucosal-associated invariant T (MAIT) cells that can overcome the current technology limitations in studying MAITs. With more detailed elucidation the identity of reprogrammed MAIT cells compared to endogenous MAITs, this paper will of broad interest to those studying the role of these cells in tumor immunity.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Understanding the biology of MAITs is a challenging for immunologists even though this cell type represent interesting functions in a variety of diseases. In this manuscript, the authors present an exciting approach with compelling data to indicate the power of reprogramming on studying MAITs as well as the therapeutic potential on harnessing MAITs for anti-tumor responses. Overall, it is well performed and aims to address interesting and important questions with excellent approaches. Although I find this manuscript interesting, I do have some concerns on the reprogramming approaches the authors applied on the detailed cellular identity. Since transcriptomic and epigenetic events are affected by reprogramming and play important role in cell identity, it would be important to determine the transcriptome and …
Reviewer #1 (Public Review):
Understanding the biology of MAITs is a challenging for immunologists even though this cell type represent interesting functions in a variety of diseases. In this manuscript, the authors present an exciting approach with compelling data to indicate the power of reprogramming on studying MAITs as well as the therapeutic potential on harnessing MAITs for anti-tumor responses. Overall, it is well performed and aims to address interesting and important questions with excellent approaches. Although I find this manuscript interesting, I do have some concerns on the reprogramming approaches the authors applied on the detailed cellular identity. Since transcriptomic and epigenetic events are affected by reprogramming and play important role in cell identity, it would be important to determine the transcriptome and chromatin accessibility in the reprogrammed MAITs and real MAITs from B6 mice. The comparisons will further strengthen the conclusion and allows the author more precisely interpret their results.
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Reviewer #2 (Public Review):
The goal of this study was to establish a system that allows the collection of MAIT cells in large quantities in order to investigate their effector functions both in vitro and in vivo.
The employment of iPSC technology to generate re-differentiated MAIT cells from endogenously differentiated bona fide MAIT cells is an elegant approach as it allows interrogation of MAIT cell functions in disease models that may not be feasible with existing TCR transgenic mice due to genetic background or other associated tools. In addition, isolation of MAIT cells in large quantity is not practical due to their low abundance relative to other T cell subsets. Thus, reMAIT cells would be a great addition to the field as a new tool to unravel the previously understudied subset of T cells with significant physiological …
Reviewer #2 (Public Review):
The goal of this study was to establish a system that allows the collection of MAIT cells in large quantities in order to investigate their effector functions both in vitro and in vivo.
The employment of iPSC technology to generate re-differentiated MAIT cells from endogenously differentiated bona fide MAIT cells is an elegant approach as it allows interrogation of MAIT cell functions in disease models that may not be feasible with existing TCR transgenic mice due to genetic background or other associated tools. In addition, isolation of MAIT cells in large quantity is not practical due to their low abundance relative to other T cell subsets. Thus, reMAIT cells would be a great addition to the field as a new tool to unravel the previously understudied subset of T cells with significant physiological importance, as the study has illustrated. The authors successfully demonstrated that (1) it is possible to generate reMAIT cells from MAIT cell-derived iPSCs just as efficiently or better than previous iPSCs generated from mouse or human T cells by others, (2) the generated reMAIT cells are viable and functional in vivo after adoptively transferring into syngeneic recipient mice, and (3) the adoptive transfer of reMAIT cells significantly improved the overall survival of mice challenged with a transplantable model of lung cancer.
However, this approach still has its limitations. Although iPSCs were obtained from endogenous bona fide MAIT cells, their re-differentiation into MAIT cells (reMAIT) was carried out in vitro without receiving certain key cell-cell communications in the thymus that may not be recapitulated. While this was necessary in order to obtain enough reMAIT cells for in vivo study by transferring them into syngeneic recipient mice, the generated reMAIT cells show some characteristics that are different from endogenous MAIT cells, such as the acquisition of maturation and tissue-resident markers like CD44 and CD69, respectively, even after two weeks post-transfer. While in vitro activation with MR1 tetramer showed the production of key cytokines and chemokines characteristic of MAIT cells, the interpretation requires the same caution as for other studies utilizing transgenic MAIT TCR mice.
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Reviewer #3 (Public Review):
In this work, Sugimoto et al. investigate the role of MAIT cells in tumor immunity, knowing the ambiguous literature describing both anti- and pro-tumoral effects of these cells in cancer. In order to overcome the paucity of these cells in mice - one of the main challenges to study them -, they use induced pluripotent stem cell technology to reprogram and redifferentiate MAIT cells. Upon adoptive transfer, the regenerated MAIT cells are capable of prolong survival in mice beared with LLC tumors through a NK-cell dependent cytolytic activity.
Overall, this is a straightforward, clearly written and well-constructed work. The rationale behind building a more relevant model to study murine MAIT cells in tumors is well introduced, especially in parallel with current studies mostly focused on Knock out or TCR …
Reviewer #3 (Public Review):
In this work, Sugimoto et al. investigate the role of MAIT cells in tumor immunity, knowing the ambiguous literature describing both anti- and pro-tumoral effects of these cells in cancer. In order to overcome the paucity of these cells in mice - one of the main challenges to study them -, they use induced pluripotent stem cell technology to reprogram and redifferentiate MAIT cells. Upon adoptive transfer, the regenerated MAIT cells are capable of prolong survival in mice beared with LLC tumors through a NK-cell dependent cytolytic activity.
Overall, this is a straightforward, clearly written and well-constructed work. The rationale behind building a more relevant model to study murine MAIT cells in tumors is well introduced, especially in parallel with current studies mostly focused on Knock out or TCR transgenic models. The data and claims are supported by controlled experiments and interesting functional insight are added regarding in vitro and in vivo interactions with NK cells.
While the adoptive transfer technique appears to be an interesting tool, it is not clear how these data issued from in vitro differentiated MAIT cells reflect their role in anti-tumor immunity (both in mice and humans). In particular, insufficient data were provided comparing regenerated MAIT vs. endogenous cells, and the constrained distribution of these cells in different tissues could affect other cells involved in anti- or pro-tumor responses.
Along the same lines, the study is based on MAIT cells stimulated with 5-OP-RU and mMR1-tet in the absence of APC, which is not representative of the actual tumor microenvironment. Knowing the impact of microbiome in cancer and the involvement of microbiota-associated antigens in MAIT TCR recognition and activation, this work could benefit from assays involving such stimuli in order to validate their role as participants of the anti-tumor immunity.
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