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.