Comparative profiling of MAIT cells across gastrointestinal cancers identifies conserved NK receptor dysregulation and HCC-specific defects in cytotoxicity and XBP1s signaling
12 affiliations
- 1Department of General and Visceral Surgery, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
- 2Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, Leipzig, Germany.
- 3Department of Radiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
- 4Department of Pathology, Vivantes Klinikum Neukölln, Berlin, Germany.
- 5Department of Visceral Surgery, Vivantes Klinikum Neukölln, Berlin, Germany.
- 6Department of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
- 7Department of Anesthesiology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
- 8Department of Urology, Evangelisches Krankenhaus Königin Elisabeth Herzberge, Berlin, Germany.
- 9Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
- 10Department of Traumatology and Reconstructive Surgery, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
- 11Department of Internal Medicine I, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany.
- 12Center of Digital Health, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
Abstract
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.
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BibTeX
@article{proß2026comparative,
title = {{Comparative profiling of MAIT cells across gastrointestinal cancers identifies conserved NK receptor dysregulation and HCC-specific defects in cytotoxicity and XBP1s signaling}},
author = {Vanessa Proß and Annkathrin Helena Ruhm and Linda Marie Laura Thole and Laura Tóth and Gishnu Harikumar Parvathy and Pia Jäger and Christina Götz and Georg Damm and Daniel Seehofer and Christian Bayerl and Hermann Herbst and Alexander Macke and Verena Frese and Akio Sakaki and Marlene Hanisch-Hernandez and Friederike Rosseck and Sascha Treskatsch and Frank Friedersdorff and Christoph Treese and Severin Daum and Dominik Laue and Benjamin Ruf and Sören Lukassen and Katja Kotsch},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1924000},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1924000/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Comparative profiling of MAIT cells across gastrointestinal cancers identifies conserved NK receptor dysregulation and HCC-specific defects in cytotoxicity and XBP1s signaling
AU - Vanessa Proß
AU - Annkathrin Helena Ruhm
AU - Linda Marie Laura Thole
AU - Laura Tóth
AU - Gishnu Harikumar Parvathy
AU - Pia Jäger
AU - Christina Götz
AU - Georg Damm
AU - Daniel Seehofer
AU - Christian Bayerl
AU - Hermann Herbst
AU - Alexander Macke
AU - Verena Frese
AU - Akio Sakaki
AU - Marlene Hanisch-Hernandez
AU - Friederike Rosseck
AU - Sascha Treskatsch
AU - Frank Friedersdorff
AU - Christoph Treese
AU - Severin Daum
AU - Dominik Laue
AU - Benjamin Ruf
AU - Sören Lukassen
AU - Katja Kotsch
PY - 2026
DA - 2026/10/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1924000
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1924000/full
AB - 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.
SN - 1664-3224
ER -