bims-maitce 2026-10-25 papers

Issue of 2026–10–25
three papers selected by
Andy E. Hogan, Maynooth University

Front Immunol. 2026 ;17 1924000

Comparative profiling of MAIT cells across gastrointestinal cancers identifies conserved NK receptor dysregulation and HCC-specific defects in cytotoxicity and XBP1s signaling.

Background & aims: Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes with cytotoxic capacity and emerging roles in tumour immunity. While MAIT cells express a diverse repertoire of natural killer (NK) receptors, the functional significance of these receptors in gastrointestinal (GI) cancers remains poorly understood.
Methods: We characterized the NK receptor repertoire and effector function of MAIT cells across five human GI tumour entities: hepatocellular carcinoma (HCC; n = 30), colorectal liver metastases (CRLM; n = 15), colorectal cancer (CRC; n = 17), pancreatic ductal adenocarcinoma (PDAC; n = 17), and gastric cancer (GC; n = 18), and examined the functional phenotype and cytotoxic potential of primary HCC-derived MAIT cells.
Results: MAIT cell frequencies varied across tumour entities and anatomical compartments, with significant intratumoral depletion in HCC compared with matched peritumoral tissue. Across all tumour entities, tumour-infiltrating MAIT cells consistently exhibited a pronounced downregulation of the activating NK receptor NKG2D. This reduction was also evident in peripheral blood MAIT cells but notably reversed following tumour resection and correlated with clinical outcomes. Functionally, IL-15-induced cytotoxicity was impaired in HCC-derived MAIT cells independently of receptor expression, suggesting additional mechanisms of dysfunction. Mechanistically, we report the expression of the endoplasmic reticulum stress-responsive transcription factor X-box binding protein 1 XBP1s (spliced form of XBP1) in circulating and tissue-resident MAIT cells. XBP1s expression was induced by IL-15 and ER stress but was attenuated in tumour-derived compared with peritumoral MAIT cells, indicating defective ER stress signalling.
Conclusions: Together, these findings define a distinct dysfunctional state of tumour-resident MAIT cells in HCC, characterized by defective ER stress responses, and identify impaired NK receptor expression across GI cancers that may contribute to impaired antitumour immunity.

Keywords: HCC; NKG2D; XBP1s; cytotoxicity; mucosa-associated invariant T cells; natural killer cell receptors

DOI: https://doi.org/10.3389/fimmu.2026.1924000

Trends Cancer. 2026 Oct 19. pii: S2405-8033(26)00220-7. [Epub ahead of print]

MAIT cells in gastrointestinal cancer: immunity to therapy.

Yan-Ruide Li, Yuning Chen, Shelby Yeh, Thomas Yuen, Lili Yang.

Mucosal-associated invariant T (MAIT) cells are emerging as important regulators of immunity in gastrointestinal (GI) cancers. Enriched in mucosal and hepatic tissues, MAIT cells recognize microbial-derived metabolites presented by MHC class I-related molecule (MR1) and rapidly exert effector functions, including cytokine production and cytotoxicity. Across GI malignancies, including hepatocellular carcinoma, cholangiocarcinoma, colorectal, gastric, pancreatic, and esophageal cancers, MAIT cells display context-dependent roles shaped by the tumor microenvironment, microbiome, and immune signaling pathways. While they can mediate antitumor immunity, they frequently exhibit functional exhaustion or adopt pro-tumorigenic phenotypes. Therapeutic strategies aim to enhance MAIT cell activity, reverse dysfunction, and integrate them into combinatorial immunotherapy approaches. Understanding MAIT cell biology may enable their exploitation as biomarkers and therapeutic targets in GI cancers.

Keywords: GI cancer; MAIT cells; MR1; TME; microbial metabolites; mucosal immunology

DOI: https://doi.org/10.1016/j.trecan.2026.09.009

Brief Bioinform. 2026 Sep 01. pii: bbag553. [Epub ahead of print]27(5):

UcTCRp: a TCRβ-based framework for identifying and profiling MAIT- and iNKT-associated repertoire signals.

Linlin Chen, Yueyi Li, Shiwen Shan, Kaixuan Wang, Chao Feng, Yunsheng Dou, Qihang Xu, Linru Cai, Hao Wang, Haiyang Wang, Xiaochen Bo, Jian Zhang.

Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells are conventionally identified using invariant or semi-invariant TCRα chains, antigen-loaded tetramers, or transcriptomic phenotypes. These requirements limit their detection in public and clinical immune-repertoire datasets that contain only TCRβ sequences. Here we present UcTCRp, a TCRβ-only framework for detecting and profiling relative MAIT- and iNKT-associated signals in bulk immune repertoires. We first identified model-informative TCRβ features, including biased V-gene usage and reproducible CDR3β amino acid composition, in collected human and mouse MAIT and iNKT TCRβ sequences. UcTCRp subsequently integrates these features using species-specific transformer-based representation pretrained separately on large human and mouse TCRβ repertoires, followed by independent supervised modeling with curated MAIT, iNKT, and conventional T cell references for each species. The resulting species-specific models generalized robustly across independent human and mouse cohorts. In paired scRNA-seq/scTCR-seq datasets, UcTCRp recovered transcriptome-defined MAIT and iNKT cells and identified additional MAIT-like candidates supported by receptor evidence but missed by expression-only annotation. Bulk calibration against paired single-cell references and synthetic spike-in experiments established operating characteristics for repertoire-level abundance estimation. These results establish unpaired TCRβ repertoires as an actionable substrate for detecting relative unconventional T cell-associated immune signals, enabling archived repertoire resources to be repurposed for systems-level studies of tissue immunity, disease, and therapeutic response.

Keywords: T cell receptor (TCR); computational immunology; deep learning; invariant natural killer T (iNKT) cells; mucosal-associated invariant T (MAIT) cells; unconventional T cells

DOI: https://doi.org/10.1093/bib/bbag553