Potential role of MAIT cells in cancer immunotherapy and viral infection

Mucosa-associated invariant T (MAIT) cells are an unconventional T cell subset with specialized antimicrobial functions. In humans, MAIT cells are characterized by their effector memory phenotype, rapid cytolytic capacity, and tissue-homing properties. Given their natural enrichment in the liver and mucosal barrier tissues, this thesis aimed to explore the potential of redirecting MAIT cells for hepatitis virus-related liver cancer immunotherapy using MHC class-I restricted T cell receptors (TCRs). Additionally, we sought to explore the role of MAIT cells in the context of another front-line immune tissue, the female genital mucosa, in human immunodeficiency virus type 1 (HIV-1) infection.

In paper I, a MAIT cell expansion methodology was developed to generate clinically relevant quantities of human MAIT cells for immunotherapies. The MAIT cell expansion protocol was highly reproducible and resulted in MAIT cell cultures with an activated phenotype, enhanced cytolytic potential, and improved tissue homing capacity. These features make them particularly suitable for solid tumour-targeting. We tested this hypothesis in paper II, by engineering expanded MAIT cells to express a TCR with specificity for hepatitis B virus (HBV). Using 2D and 3D hepatoma cell models of HBV-related hepatocellular carcinoma, we compared the antiviral, cytotoxic, and tumour homing properties of the TCR-redirected MAIT cells with those of conventional T cells currently being used in the clinic. We demonstrated that the MAIT cells not only acquired a distinct polyfunctional antigen-specific profile in response to HBV, but also retained their antimicrobial properties, and readily migrated towards the tumor targets in a 3D microfluidic model. In paper III, we investigated the phenotype of MAIT cells in women living with chronic HIV-1 infection. We initially confirmed that circulating MAIT cells were activated and numerically depleted in the blood. However, MAIT cells were preserved in the cervical mucosa. The TRAV1-2-TRAJ20 MAIT TCR transcript was highly expressed in the ectocervix and was significantly upregulated in the HIV-1 infected women relative to uninfected controls. This indicates that MAIT cells may be poised to recognize stimuli unique to that environment, and that HIV-1 infection may shape the MAIT cell population in the female genital tract.

In summary, the research covered by this thesis demonstrates the potential role of MAIT cells in the context of virus-related cancer immunotherapy and barrier tissue infiltration. Taken together, these findings illuminate new avenues of research in MAIT cell biology in human health and disease.

List of scientific papers

I. Parrot T, Healy K, Boulouis C, Sobkowiak MJ, Leeansyah E, Aleman S, Bertoletti A, Sällberg Chen M, Sandberg JK. Expansion of donor-unrestricted MAIT cells with enhanced cytolytic function suitable for TCR-redirection. JCI Insight. 2021 Feb 9:140074.
https://doi.org/10.1172/jci.insight.140074

II. Healy K, Pavesi A, Parrot T, Sobkowiak MJ, Reinsbach SE, Davanian H, Tan AT, Aleman S, Sandberg JK, Bertoletti A, Sällberg Chen M. Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBVHCC while retaining antimicrobial functions. JHEP Rep. 2021; 3:100318.
https://doi.org/10.1016/j.jhepr.2021.100318

III. Gibbs A*, Healy K*, Kaldhusdal V, Sundling C, Franzén-Boger M, Edfeldt G, Buggert M, Lajoie J, Fowke K, Kimani J, Kwon D, Andersson S, Sandberg JK, Broliden K, Davanian H, Sällberg Chen M, Tjernlund A. MAIT cells are preserved in the cervical mucosa of HIV infected women and exhibit a dominant usage of the Vα7.2-Jα20 TCR. *Shared contribution. [Manuscript]