Engineering Human MAIT Cells with Chimeric Antigen Receptors for Cancer Immunotherapy.

Abstract

Engineering immune cells with chimeric Ag receptors (CARs) is a promising technology in cancer immunotherapy. Besides classical cytotoxic CD8+ T cells, innate cell types such as NK cells have also been used to generate CAR-T or CAR-NK cells. In this study, we devised an approach to program a nonclassical cytotoxic T cell subset called mucosal-associated invariant T (MAIT) cells into effective CAR-T cells against B cell lymphoma and breast cancer cells. Accordingly, we expressed anti-CD19 and anti-Her2 CARs in activated primary human MAIT cells and CD8+ T cells, expanded them in vitro, and compared their cytotoxicity against tumor cell targets. We show upon activation through CARs that CAR-MAIT cells exhibit high levels of cytotoxicity toward target cells, comparable to CD8+ CAR-T cells, but interestingly expressed lower levels of IFN-γ than conventional CAR CD8+ T cells. Additionally, in the presence of vitamin B2 metabolite 5-ARU (5-amino-4-d-ribitylaminouracil dihydrochloride), which is a conserved compound that activates MAIT cells through MHC class I-related (MR1) protein, MAIT cells killed MR1-expressing target breast cancer and B cell lymphoma cell lines in a dose-dependent manner. Thus, MAIT cells can be genetically edited as CAR-T cells or mobilized and expanded by MR1 ligands as an off-the-shelf novel approach to cell-based cancer immunotherapy strategies while being comparable to conventional methods in effectivity.

• Authors: Mikail Dogan, Ece Karhan, Lina Kozhaya, Lindsey Placek, Xin Chen, Mesut Yigit, Derya Unutmaz
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 209 Issue 8 Pg. 1523-1531 (10 15 2022) ISSN: 1550-6606 [Electronic] United States
• PMID: 36165183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 by The American Association of Immunologists, Inc.

Chemical References

• Antigens
• Histocompatibility Antigens Class I
• Minor Histocompatibility Antigens
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen
• Vitamins

Topics

• Antigens (metabolism)
• Breast Neoplasms (therapy)
• CD8-Positive T-Lymphocytes
• Female
• Histocompatibility Antigens Class I
• Humans
• Immunotherapy
• Lymphoma, B-Cell
• Minor Histocompatibility Antigens (genetics)
• Mucosal-Associated Invariant T Cells
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen
• Vitamins