The use of chimeric antigen receptor-engineered T cells (CAR-T) in antitumor immunology has made substantial progress in the last decade. However, there are persistent challenges to widespread adoption and implementation of these therapies, namely, graft-versus-host disease (GvHD) and tumor-associated immunosuppression. This has inspired researchers to explore unconventional T cells, a specialized subset of T lymphocytes that may have important roles in antitumor immunity.
Human mucosal-associated invariant T (MAIT) cells are one such population of unconventional T cells. They have been shown to influence various cancers, bacterial and viral infections, and autoimmune, inflammatory, and metabolic diseases significantly. MAIT cells are a relatively new discovery compared to other types of unconventional T cells, and their potential to treat cancer and other diseases could be a game-changer in personalized medicine. Researchers are making progress in using allogeneic these cells as “off-the-shelf” immunotherapies instead of costly individualized CAR-T cell harvesting and reinfusion.
How MAIT cells function differently than other T cells
MAIT cells are predominantly found in mucosal tissues like the lungs and gut, but they’re also present in skin, adipose tissue, and the liver. Unlike conventional T cells, MAIT cells are not restricted by major histocompatibility complex (MHC) molecules, but recognize the MHC-related protein 1 (MR1). They express a semi-invariant TCR α-chain (Vα7.2-Jα33/20/12 in humans) and a limited range of TCR-β chains, mainly from the TRBV20 and TRBV6 gene families.
Approximately 80% of MAIT cells in healthy adults express CD8, while 15% are double negative (CD4-CD8-), with less than 5% expressing CD4 or double positives (CD4+CD8+). As seen in Figure 1, MAIT cells contain numerous biomarkers, such as identification, activation, co-stimulatory, coinhibitory, and immunotherapy target molecule PD-1.
MAIT cells can be activated through two distinct pathways: one dependent on T-cell receptors (TCR) and the other independent of them(see Figure 2). The TCR-dependent pathway is initiated by the presentation of antigens, such as 5-OE-RU and 5-OP-RU, on MR1 cells, which can include various antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells. This engagement leads to the activation of MAIT cells, characterized by the upregulation of markers such as CD25, CD69, CD38, and HLA-DR, and the production of TNF-α and/or IL-17.
Conversely, MAIT cells can also be activated by cytokines like IL-7, IL-12, IL-15, and IL-18, which do not require TCR engagement. TCR-dependent activation results in greater production of inflammatory cytokines compared to TCR-independent activation. Both pathways can induce degranulation, marked by CD107a, and the release of granzyme A, B, K, H, M, and perforin on target cells.
We analyzed the CAS Content CollectionTM, the largest human-curated repository of scientific information, and found a surge in studies investigating the therapeutic potential of MAIT cells starting in 2016. These studies cover cancer, autoimmune diseases, and immunotherapy, as well as post-transplant scenarios and chronic infections. The patent landscape for MAIT cells has also been expanding in just the last five years (see Figure 3).
Such precipitous growth suggests that MAIT cell therapies are making progress toward commercialization. For example, one notable patent application (CN118853585A) involves MAIT cells expressing CARs for treating cancer, infectious diseases, and autoimmune diseases. This innovation relates to MAIT cells expressing a CAR, wherein the MAIT cells are allogeneic to a subject to be treated, an important breakthrough in targeted therapies. If MAIT cells can be developed from donors and not crafted for each patient, these therapies can be expanded to more patients cost-effectively.
Potential MAIT cell treatments in oncology and beyond
We analyzed key concepts related to MAIT cells in the CAS Content Collection, and cancer is the most extensively studied, accounting for nearly half of the publications (see Figure 4). The predominant cancers include hematological, gastrointestinal tract, lung, gynecological, and skin cancers. Apart from cancer, MAIT cells are also researched in the context of inflammatory diseases (15%), autoimmune diseases (13%), viral diseases (9%), bacterial infections (6%), and many other conditions such as lung diseases, liver diseases, metabolic disorders, immune diseases, blood disorders, and fibrosis. These insights underscore the diverse roles of MAIT cells in various diseases and their potential as therapeutic targets.
MAIT cells in cancer immunotherapy
MAIT cells use various tumor-targeting mechanisms, such as CAR, TCR, and NKR-mediated cytotoxicity, allowing them to identify and destroy many types of tumor cells while reducing the risk of tumor antigen escape. Additionally, because they have not shown alloreactive adverse reactions, MAIT cells have the potential to be the main cell type in the future of adoptive off-the-shelf cancer immunotherapies, overcoming barriers of human leukocyte antigen (HLA) disparity.
Below are the unique properties and functions of MAIT cells that make them promising for cancer immunotherapy:
- Multiple tumor-targeting mechanisms: MAIT cells can attack tumors through:
- Direct killing of MR1+ tumor cells through MR1/TCR recognition.
- Killing of MR1- tumor cells through the NK pathway as MAIT cells express activating NK receptors such as NKG2D and DNAM-1, which may recognize NK-related stress ligands (MIC-A/B and/or ULBP-1) present on tumor cells and confer NK-mediated cytotoxicity.
- Boosting dendritic cell (DC) activation, which leads to the upregulation of CD40L and activation of NK cells and effector T cells, thereby amplifying the immune response.
- Inhibition of tumor-associated macrophage (TAMs) and myeloid-derived suppressor cells (MDSCs).
- Potential for genetic engineering: The adaptability of MAIT cells to genetic modifications, such as cytokine engineering and checkpoint gene knockout, enables the enhancement of their functional properties. This includes extended persistence, improved cytotoxicity, and increased resistance to the immunosuppressive environment of the tumor microenvironment.
- Graft-versus-host disease (GvHD) amelioration: MAIT cells are restricted by MR1 and do not recognize mismatched HLA molecules and protein autoantigens. Therefore, MAIT cells are not expected to induce GvHD. CD19 CAR-MAIT cells were safely engrafted in preclinical mouse models without causing GvHD, unlike CD19 CAR-T cells.
- Cancer drug resistance: MAIT cells are more resistant to chemotherapy in comparison with other T cell subtypes, as these cells could rapidly efflux various chemotherapeutic drugs. This resistance suggests MAIT cells are a promising alternative cell source for the development of autologous CAR-T cell therapy, since current cancer patients qualified for receiving autologous CAR-T cell therapy must have received several first-line treatments, particularly chemotherapy.
- Potential target for anti-PD-1/PD-L1 immunotherapy: Immune checkpoint inhibitors (ICIs) such as anti-PD-1 therapy have achieved significant therapeutic efficacy in many malignant diseases. MAIT cells express many of the targets of ICIs, highlighting the potential importance of these cells in ICIs immunotherapy. An in vivo study reported that MAIT cell activation, combined with anti-PD-L1 therapy, reduced tumor growth in wild-type mice but not in Mr1-/- mice, indicating that combination therapy using both ICIs and ex vivo activated MAIT cells might provide a novel strategy to boost the efficacy of ICI treatments such as anti-PD-1 therapy.
- Prognostic marker: Researchers observed an increased frequency of MAIT cells in cancer patients at baseline and after anti-PD-1 therapy. This correlated with a favorable response to anti-PD-1 therapy in both multiple myeloma and melanoma patients. Thus, the presence and frequency of MAIT cells can serve as biomarkers for predicting patient responses to certain cancer therapies.
MAIT cells in immune-mediated inflammatory diseases
In autoimmune disorders where MAIT cells primarily contribute to disease pathology, selectively suppressing these cells is a promising therapeutic approach. Researchers have identified specific compounds, such as acetyl-6-formylpterin, that function as potent inhibitory ligands for MAIT cells. The development of such targeted MAIT cell inhibitors presents an opportunity for pharmaceutical research, potentially leading to more precise interventions for autoimmune conditions where MAIT cell hyperactivity drives inflammation and tissue damage.
MAIT cells in antiviral defense
Recent advancements have demonstrated that MAIT cells can react to various viral infections in humans and mouse models, including HIV-1, hepatitis viruses, influenza virus, and SARS-CoV-2, primarily in an antigen-independent manner. Depending on the disease context, MAIT cells can offer direct or indirect antiviral protection for the host and may assist in recruiting other immune cells. However, in certain situations, they might also exacerbate inflammation and worsen immunopathology. Additionally, chronic viral infections are linked to varying levels of functional and numerical impairment of MAIT cells, indicating potential secondary effects on host defense.
MAIT cells as promising vaccine components
MAIT cells offer unique advantages for vaccine development due to their abundance, pre-existing effector memory phenotype, mucosal location, and conserved T cell receptors. Mouse studies show MAIT cell populations can be rapidly expanded using specific ligands with co-stimulatory signals, potentially enhancing localized immune responses against respiratory infections. The development of stable MAIT cell-activating compounds could significantly advance prophylactic vaccines by serving as biological adjuvants when added to conventional B or T cell vaccines. This approach could improve vaccine efficacy by utilizing MAIT cells' quick response capabilities and strategic positioning at infection entry sites. Ongoing research into stable MAIT cell ligands represents a promising direction in vaccination technology.
MAIT cells in wound healing
MAIT cells' newly discovered role in wound healing offers promising clinical applications for patients with chronic skin wounds like leg ulcers, pressure sores, and burns. Two potential therapeutic strategies have emerged: introducing riboflavin-producing commensal bacteria to wound sites to naturally activate MAIT cells or directly applying synthetic MAIT cell-activating compounds topically. The latter approach has shown success in mouse studies, providing proof-of-concept validation.
This treatment approach is attractive due to its straightforward clinical implementation pathway. The topical application method and established safety profile of many MAIT cell ligands could facilitate rapid progression to large-scale clinical trials, potentially transforming treatment options for persistent wounds that traditionally heal slowly.
Next steps for MAIT cell therapies
CAR-MAIT cells have been developed in preclinical studies, and evidence highlights the feasibility of their antitumor activity. However, there haven’t been any clinical trials to explore their application in cancer treatment. It will take time to conduct the necessary clinical trials, but the possibility of MAIT cells functioning as an off-the-shelf CAR-T therapy is extremely promising. Biotechnology company Pluri, in collaboration with the Bar-Ilan University Research and Development Company (BIRAD), is developing allogeneic, off-the-shelf, placental-derived CAR-MAIT cells to treat solid tumors, suggesting that breakthrough therapies may be close.
CAR-T therapies to date have involved extracting, modifying, and reinfusing T cells from each individual patient, a process that is costly and time-consuming. If MAIT cells could be engineered to attack tumors in any patient, it would mark a significant step forward in making these therapies available to more patients.
