Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy
Abstract
:1. Introduction
2. General Features of MAIT Cells
3. MAIT Cells in Human Cancer
4. Pro-Tumor and Anti-Tumor Functions of MAIT Cells in Mucosal Cancers
5. Pro-Tumor and Anti-Tumor Functions of MAIT Cells in Other Cancers
6. MAIT Cells and Microbiota in Cancer
7. MAIT Cells in Murine Cancer Models
8. iPSC-Derived MAIT Cells (m-reMAIT Cells) in Murine Cancer Models
9. Therapy for Cancer with reMAIT Cells
- MAIT cells (more precisely m-reMAIT cells) exert cytotoxic activity against tumor cells without an agonist. MAIT-like cells can be differentiated from human iPSCs (referred as reMAIT cells) [45]. This ensures the preparation of a theoretically unlimited number of reMAIT cells for cell therapy.
- MR1, the molecule responsible for restricting MAIT cell development and proliferation, is monomorphic, unlike MHC I and II, which are polymorphic in nature. Such a feature ensures that the responsiveness of TCR is equivalent among individuals, whereas that of conventional T cells varies from one person to another.
- MAIT cells are reluctant to cause graft-versus-host disease (GvHD) and are cancer-drug resistant. These features add more value to the immune cell therapy, in that allogenic MAIT cells could be used as universal cells for adoptive transfer together with anti-cancer drugs [1,46]. Indeed, in anthracycline-treated cancer patients, MAIT cell number remains intact after drug regimen, while many, if not all, conventional T cells are eliminated. The drug-resistance of MAIT cells is conferred by the presence of a multidrug efflux pump such as CD243.
- MAIT cells could serve as an adjuvant for bolstering anti-tumor immunity by reinforcing expansion and the effector functions of NK cells.
9.1. Future Directions Towards Designer MAIT Cells
9.2. Issues to Be Addressed in the near Future
- While m-reMAIT cells kill Yac-1 and LLC, whether reMAIT cells (human iPSCs-derived MAIT-like cells) exert cytotoxic activity against an array of human tumor cells, as MR1-T cells do, should be determined. In this case, it is also important to determine whether the cytotoxic activity is dependent on 5-OP-RU or not, in other words, TCR-dependent or independent.
- Whether m-reMAIT cells and reMAIT cells have an anti-tumor effect in therapeutic models should be addressed. Present data only demonstrate that adoptive transfer of m-reMAIT cells prior to tumor inoculation inhibits tumor growth and prolongs mouse survival. It is thus imperative to examine whether adoptive transfer of m-reMAIT cells and/or reMAIT cells after tumor inoculation also engenders inhibition of tumor expansion (therapeutic model).
- Whether CAR-MAIT cells and/or CAR-reMAIT cells exert much stronger anti-tumor effects, including cytotoxic activity, than MAIT cells and/or reMAIT cells in both prophylaxis and therapeutic models should also be interrogated.
- Since MAIT cells are thought not to induce GvHD, it is necessary to examine whether this is also applicable to CAR-MAIT cells and/or CAR-reMAIT cells.
- As CAR-T cells could last for more than a decade after transfer into humans [53], it is also compulsory to examine how long CAR-MAIT cells and/or CAR-reMAIT cells survive in highly immunocompromised mice, such as NOG or NSG mice.
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
- Dusseaux, M.; Martin, E.; Serriari, N.; Péguillet, I.; Premel, V.; Louis, D.; Milder, M.; Le Bourhis, L.; Soudais, C.; Treiner, E.; et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells. Blood 2011, 117, 1250–1259. [Google Scholar] [CrossRef] [PubMed]
- Zheng, L.; Qin, S.; Si, W.; Wang, A.; Xing, B.; Gao, R.; Ren, X.; Wang, L.; Wu, X.; Zhang, J.; et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 2021, 374, abe6474. [Google Scholar] [CrossRef] [PubMed]
- Godfrey, D.I.; Le Nours, J.; Andrews, D.M.; Uldrich, A.P.; Rossjohn, J. Unconventional T Cell Targets for Cancer Immunotherapy. Immunity 2018, 48, 453–473. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ambrosino, E.; Terabe, M.; Halder, R.C.; Peng, J.; Takaku, S.; Miyake, S.; Yamamura, T.; Kumar, V.; Berzofsky, J.A. Cross-Regulation between Type I and Type II NKT Cells in Regulating Tumor Immunity: A New Immunoregulatory Axis. J. Immunol. 2007, 179, 5126–5136. [Google Scholar] [CrossRef] [Green Version]
- Lawrence, M.; Wiesheu, R.; Coffelt, S.B. The duplexity of unconventional T cells in cancer. Int. J. Biochem. Cell Biol. 2022, 146, 106213. [Google Scholar] [CrossRef]
- Sugimoto, C.; Murakami, Y.; Ishii, E.; Fujita, H.; Wakao, H. Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity. eLife 2022, 11, e70848. [Google Scholar] [CrossRef]
- Godfrey, D.I.; Koay, H.; McCluskey, J.; Gherardin, N.A. The biology and functional importance of MAIT cells. Nat. Immunol. 2019, 20, 1110–1128. [Google Scholar] [CrossRef]
- Tilloy, F.; Treiner, E.; Park, S.H.; Garcia, C.; Lemonnier, F.; de la Salle, H.; Bendelac, A.; Bonneville, M.; Lantz, O. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals. J. Exp. Med. 1999, 189, 1907–1921. [Google Scholar] [CrossRef] [Green Version]
- Reantragoon, R.; Corbett, A.J.; Sakala, I.G.; Gherardin, N.A.; Furness, J.B.; Chen, Z.; Eckle, S.B.G.; Uldrich, A.P.; Birkinshaw, R.W.; Patel, O.; et al. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J. Exp. Med. 2013, 210, 2305–2320. [Google Scholar] [CrossRef]
- Böttcher, K.; Rombouts, K.; Saffioti, F.; Roccarina, D.; Rosselli, M.; Hall, A.; Luong, T.; Tsochatzis, E.A.; Thorburn, D.; Pinzani, M. MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation. Hepatology 2018, 68, 172–186. [Google Scholar] [CrossRef]
- Cogswell, D.T.; Gapin, L.; Tobin, H.M.; McCarter, M.D.; Tobin, R.P. MAIT Cells: Partners or Enemies in Cancer Immunotherapy? Cancers 2021, 13, 1502. [Google Scholar] [CrossRef] [PubMed]
- Fernandez, C.S.; Amarasena, T.; Kelleher, A.D.; Rossjohn, J.; McCluskey, J.; Godfrey, D.I.; Kent, S.J. MAIT cells are depleted early but retain functional cytokine expression in HIV infection. Immunol. Cell Biol. 2015, 93, 177–188. [Google Scholar] [CrossRef]
- Berkson, J.D.; Slichter, C.K.; DeBerg, H.A.; Delaney, M.A.; Woodward-Davis, A.S.; Maurice, N.J.; Lwo, Y.; Ko, A.; Hsu, J.; Chiu, Y.; et al. Inflammatory Cytokines Induce Sustained CTLA-4 Cell Surface Expression on Human MAIT Cells. ImmunoHorizons 2020, 4, 14–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eberl, G. RORγt, a multitask nuclear receptor at mucosal surfaces. Mucosal Immunol. 2017, 10, 27–34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Intlekofer, A.; Takemoto, N.; Wherry, E.; Longworth, S.; Northrup, J.; Palanivel, V.; Mullen, A.; Gasink, C.; Kaech, S.; Miller, J.; et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 2005, 6, 1236–1244. [Google Scholar] [CrossRef] [PubMed]
- Rahimpour, A.; Koay, H.F.; Enders, A.; Clanchy, R.; Eckle, S.B.G.; Meehan, B.; Chen, Z.; Whittle, B.; Liu, L.; Fairlie, D.P.; et al. Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers. J. Exp. Med. 2015, 212, 1095–1108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Treiner, E.; Duban, L.; Bahram, S.; Radosavljevic, M.; Wanner, V.; Tilloy, F.; Affaticati, P.; Gilfillan, S.; Lantz, O. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 2003, 422, 164–169. [Google Scholar] [CrossRef]
- Koay, H.; Su, S.; Amann-Zalcenstein, D.; Daley, S.R.; Comerford, I.; Miosge, L.; Whyte, C.E.; Konstantinov, I.E.; d’Udekem, Y.; Baldwin, T.; et al. A divergent transcriptional landscape underpins the development and functional branching of MAIT cells. Sci. Immunol. 2019, 4, eaay6039. [Google Scholar] [CrossRef]
- Kjer-Nielsen, L.; Patel, O.; Corbett, A.J.; Le Nours, J.; Meehan, B.; Liu, L.; Bhati, M.; Chen, Z.; Kostenko, L.; Reatragoon, R.; et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 2012, 491, 717–723. [Google Scholar] [CrossRef] [Green Version]
- Corbett, A.J.; Eckle, S.B.G.; Birkinshaw, R.W.; Liu, L.; Patel, O.; Mahony, J.; Chen, Z.; Reantragoon, R.; Meehan, B.; Cao, H.; et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 2014, 509, 361–365. [Google Scholar] [CrossRef]
- Legoux, F.; Bellet, D.; Daviaud, C.; El Morr, Y.; Darbois, A.; Niort, K.; Procopio, E.; Salou, M.; Gilet, J.; Ryffel, B.; et al. Microbial metabolites control the thymic development of mucosal-associated invariant T cells. Science 2019, 366, 494–499. [Google Scholar] [CrossRef] [PubMed]
- Koay, H.; Gherardin, N.A.; Enders, A.; Loh, L.; Mackay, L.K.; Almeida, C.F.; Russ, B.E.; Nold-Petry, C.A.; Nold, M.F.; Bedoui, S.; et al. A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage. Nat. Immunol. 2016, 17, 1300–1311. [Google Scholar] [CrossRef] [PubMed]
- Ussher, J.E.; Bilton, M.; Attwod, E.; Shadwell, J.; Richardson, R.; Lara, C.; Mettke, E.; Kurioka, A.; Hansen, T.H.; Klenerman, P.; et al. CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur. J. Immunol. 2014, 44, 195–203. [Google Scholar] [CrossRef] [PubMed]
- Lamichhane, R.; Schneider, M.; de la Harpe, S.M.; Harrop, T.W.R.; Hannaway, R.F.; Dearden, P.K.; Kirman, J.R.; Tyndall, J.D.A.; Vernall, A.J.; Ussher, J.E. TCR- or Cytokine-Activated CD8+ Mucosal-Associated Invariant T Cells Are Rapid Polyfunctional Effectors That Can Coordinate Immune Responses. Cell Rep. 2019, 28, 3061–3076.e5. [Google Scholar] [CrossRef] [Green Version]
- Peterfalvi, A.; Gomori, E.; Magyarlaki, T.; Pal, J.; Banati, M.; Javorhazy, A.; Szekeres-Bartho, J.; Szereday, L.; Illes, Z. Invariant Vα7.2-Jα33 TCR is expressed in human kidney and brain tumors indicating infiltration by mucosal-associated invariant T (MAIT) cells. Int. Immunol. 2008, 20, 1517–1525. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zabijak, L.; Attencourt, C.; Guignant, C.; Chatelain, D.; Marcelo, P.; Marolleau, J.; Treiner, E. Increased tumor infiltration by mucosal-associated invariant T cells correlates with poor survival in colorectal cancer patients. Cancer Immunol. Immunother. 2015, 64, 1601–1608. [Google Scholar] [CrossRef]
- Sundström, P.; Ahlmanner, F.; Akéus, P.; Sundquist, M.; Alsén, S.; Yrlid, U.; Börjesson, L.; Sjöling, Å.; Gustavsson, B.; Wong, S.B.J.; et al. Human mucosa-associated invariant T cells accumulate in colon adenocarcinomas but produce reduced amounts of IFN-γ. J. Immunol. 2015, 195, 3472–3481. [Google Scholar] [CrossRef] [Green Version]
- Sundström, P.; Szeponik, L.; Ahlmanner, F.; Sundquist, M.; Wong, J.S.B.; Lindskog, E.B.; Gustafsson, B.; Quiding-Järbrink, M. Tumor-infiltrating mucosal-associated invariant T (MAIT) cells retain expression of cytotoxic effector molecules. Oncotarget 2019, 10, 2810–2823. [Google Scholar] [CrossRef] [Green Version]
- Ling, L.; Lin, Y.; Zheng, W.; Hong, S.; Tang, X.; Zhao, P.; Li, M.; Ni, J.; Li, C.; Wang, L.; et al. Circulating and tumor-infiltrating mucosal associated invariant T (MAIT) cells in colorectal cancer patients. Sci. Rep. 2016, 6, 20358. [Google Scholar] [CrossRef] [Green Version]
- Zheng, C.; Zheng, L.; Yoo, J.; Guo, H.; Zhang, Y.; Guo, X.; Kang, B.; Hu, R.; Huang, J.Y.; Zhang, Q.; et al. Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell 2017, 169, 1342–1356.e16. [Google Scholar] [CrossRef]
- Duan, M.; Goswami, S.; Shi, J.; Wu, L.; Wang, X.; Ma, J.; Zhang, Z.; Shi, Y.; Ma, L.; Zhang, S.; et al. Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma. Clin. Cancer Res. 2019, 25, 3304–3316. [Google Scholar] [CrossRef] [Green Version]
- Zimmer, C.L.; Filipovic, I.; Cornillet, M.; O’Rourke, C.J.; Berglin, L.; Jansson, H.; Sun, D.; Strauss, O.; Hertwig, L.; Johansson, H.; et al. Mucosal-associated invariant T-cell tumor infiltration predicts long-term survival in cholangiocarcinoma. Hepatology 2022, 75, 1154–1168. [Google Scholar] [CrossRef]
- Gherardin, N.A.; Loh, L.; Admojo, L.; Davenport, A.J.; Richardson, K.; Rogers, A.; Darcy, P.K.; Jenkins, M.R.; Prince, H.M.; Harrison, S.J.; et al. Enumeration functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma. Sci. Rep. 2018, 8, 4159. [Google Scholar] [CrossRef] [Green Version]
- Zumwalde, N.A.; Haag, J.D.; Gould, M.N.; Gumperz, J.E. Mucosal associated invariant T cells from human breast ducts mediate a Th17-skewed response to bacterially exposed breast carcinoma cells. Breast Cancer Res. BCR 2018, 20, 111. [Google Scholar] [CrossRef]
- Li, S.; Simoni, Y.; Becht, E.; Loh, C.Y.; Li, N.; Lachance, D.; Koo, S.; Lim, T.P.; Tan, E.K.W.; Mathew, R.; et al. Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer. Cell Rep. Med. 2020, 1, 100039. [Google Scholar] [CrossRef]
- Yan, J.; Allen, S.; McDonald, E.; Das, I.; Mak, J.Y.W.; Liu, L.; Fairlie, D.P.; Meehan, B.S.; Chen, Z.; Corbett, A.J.; et al. MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1. Cancer Discov. 2020, 10, 124–141. [Google Scholar] [CrossRef]
- Cui, J.; Shin, T.; Kawano, T.; Sato, H.; Kondo, E.; Toura, I.; Kaneko, Y.; Koseki, H.; Kanno, M.; Taniguchi, M. Requirement for Vα14 NKT Cells in IL-12-Mediated Rejection of Tumors. Science 1997, 278, 1623. [Google Scholar] [CrossRef]
- Petley, E.V.; Koay, H.; Henderson, M.A.; Sek, K.; Todd, K.L.; Keam, S.P.; Lai, J.; House, I.G.; Li, J.; Zethoven, M.; et al. MAIT cells regulate NK cell-mediated tumor immunity. Nat. Commun. 2021, 12, 4746. [Google Scholar] [CrossRef]
- Ruf, B.; Catania, V.V.; Wabitsch, S.; Ma, C.; Diggs, L.P.; Zhang, Q.; Heinrich, B.; Subramanyam, V.; Cui, L.L.; Pouzolles, M.; et al. Activating Mucosal-Associated Invariant T Cells Induces a Broad Antitumor Response. Cancer Immunol. Res. 2021, 9, 1024–1034. [Google Scholar] [CrossRef]
- Rudak, P.T.; Choi, J.; Haeryfar, S.M.M. MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer. J. Leukoc. Biol. 2018, 104, 473–486. [Google Scholar] [CrossRef]
- Le Bourhis, L.; Dusseaux, M.; Bohineust, A.; Bessoles, S.; Martin, E.; Premel, V.; Coré, M.; Sleurs, D.; Serriari, N.; Treiner, E.; et al. MAIT Cells Detect and Efficiently Lyse Bacterially-Infected Epithelial Cells. PLoS Pathog. 2013, 9, e1003681. [Google Scholar] [CrossRef] [Green Version]
- Song, Y.; Yang, J.M. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer. Biochem. Biophys. Res. Commun. 2017, 493, 1–8. [Google Scholar] [CrossRef]
- Fisher, D.T.; Appenheimer, M.M.; Evans, S.S. The two faces of IL-6 in the tumor microenvironment. Semin. Immunol. 2014, 26, 38–47. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Li, M.; Zhou, K.; Brown, J.; Tsao, T.; Cen, X.; Husman, T.; Bajpai, A.; Dunn, Z.S.; Yang, L. Engineering Induced Pluripotent Stem Cells for Cancer Immunotherapy. Cancers 2022, 14, 2266. [Google Scholar] [CrossRef]
- Wakao, H.; Yoshikiyo, K.; Koshimizu, U.; Furukawa, T.; Enomoto, K.; Matsunaga, T.; Tanaka, T.; Yasutomi, Y.; Yamada, T.; Minakami, H.; et al. Expansion of Functional Human Mucosal-Associated Invariant T Cells via Reprogramming to Pluripotency and Redifferentiation. Cell Stem Cell 2013, 12, 546–558. [Google Scholar] [CrossRef] [Green Version]
- Bohineust, A.; Tourret, M.; Derivry, L.; Caillat-Zucman, S. Mucosal-associated invariant T (MAIT) cells, a new source of universal immune cells for chimeric antigen receptor (CAR)-cell therapy. Bull. Du Cancer 2021, 108, S92–S95. [Google Scholar] [CrossRef]
- Crowther, M.D.; Dolton, G.; Legut, M.; Caillaud, M.E.; Lloyd, A.; Attaf, M.; Galloway, S.A.E.; Rius, C.; Farrell, C.P.; Szomolay, B.; et al. Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat. Immunol. 2020, 21, 178–185. [Google Scholar] [CrossRef]
- Qin, V.M.; D’Souza, C.; Neeson, P.J.; Zhu, J.J. Chimeric Antigen Receptor beyond CAR-T Cells. Cancers 2021, 13, 404. [Google Scholar] [CrossRef]
- Dogan, M.; Karhan, E.; Kozhaya, L.; Placek, L.; Chen, X.; Yigit, M.; Unutmaz, D. Engineering Human MAIT Cells with Chimeric Antigen Receptors for Cancer Immunotherapy. J. Immunol. 2022, 209, 1523–1531. [Google Scholar] [CrossRef]
- Sterner, R.M.; Sakemura, R.; Cox, M.J.; Yang, N.; Khadka, R.H.; Forsman, C.L.; Hansen, M.J.; Jin, F.; Ayasoufi, K.; Hefazi, M.; et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 2019, 133, 697–709. [Google Scholar] [CrossRef]
- Sade-Feldman, M.; Yizhak, K.; Bjorgaard, S.L.; Ray, J.P.; de Boer, C.G.; Jenkins, R.W.; Lieb, D.J.; Chen, J.H.; Frederick, D.T.; Barzily-Rokni, M.; et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2019, 176, 404. [Google Scholar] [CrossRef] [Green Version]
- Biasi, S.D.; Gibellini, L.; Tartaro, D.L.; Puccio, S.; Rabacchi, C.; Mazza, E.M.C.; Brummelman, J.; Williams, B.; Kaihara, K.; Forcato, M.; et al. Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy. Nat. Commun. 2021, 12, 1669. [Google Scholar] [CrossRef]
- Melenhorst, J.J.; Chen, G.M.; Wang, M.; Porter, D.L.; Chen, C.; Collins, M.A.; Gao, P.; Bandyopadhyay, S.; Sun, H.; Zhao, Z.; et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 2022, 602, 503–509. [Google Scholar] [CrossRef]
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Sugimoto, C.; Fujita, H.; Wakao, H. Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy. Biomedicines 2022, 10, 3160. https://doi.org/10.3390/biomedicines10123160
Sugimoto C, Fujita H, Wakao H. Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy. Biomedicines. 2022; 10(12):3160. https://doi.org/10.3390/biomedicines10123160
Chicago/Turabian StyleSugimoto, Chie, Hiroyoshi Fujita, and Hiroshi Wakao. 2022. "Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy" Biomedicines 10, no. 12: 3160. https://doi.org/10.3390/biomedicines10123160
APA StyleSugimoto, C., Fujita, H., & Wakao, H. (2022). Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy. Biomedicines, 10(12), 3160. https://doi.org/10.3390/biomedicines10123160