Margaret Sällberg Chen is a Full Professor at Karolinska Institutet (KI), where she serves as Faculty Representative for Doctoral Education. She leads a research group at the Division of Pathology, LABMED, focusing on immunology and microbiome-host interactions, and holds an adjunct professorship at the Karolinska Comprehensive Cancer Center, specializing in cell therapy and allogeneic stem cell transplantation.
Her research focues on translational immunology, with a strong emphasis on cancer immunology, infectious diseases, and microbiome research. Recently, her team has explored the interplay between the microbiota and immune responses in the context of cancer and oncopathogens, including the development of biomarkers for diagnostics and therapeutics.
She has authored 97 peer-reviewed publications and co-authored several book chapters and magazines, with over 4,700 citations and an h-index of 33. She has supervised numerous PhD students and postdoctoral researchers, and her work is supported by leading Swedish and international funding agencies.
She has extensive international collaborations in cancer immunology and regenerative medicine, and has held academic guest positions at institutions such as the National Institutes of Health (NIH), Nanyang Technological University (NTU) Singapore, Tongji University, and Cancer Research UK through collaborations.
Harnessing MAIT cells for immunotherapy against oncogenic microbiota-associated tumors
Margaret Sällberg Chen1,2.
1Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; 2Cell Therapy and Allogeneic Stem Cell Transplantation (ME CAST), Karolinska University Hospital, Huddinge, Sweden
Introduction: Emerging evidence supports the presence of distinct intratumoral microbiota in several solid malignancies, including liver and pancreatic cancers. These tumor-associated microbial communities contribute to cancer progression, chemoresistance, and genomic instability through induction of oncogenic metabolites and inflammation. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that sense microbial metabolic imbalances, and altered MAIT cell biodistribution and functional impairments are commonly observed in gastrointestinal cancer patients.
Methods: We developed a robust ex vivo methodology to generate clinically relevant quantities of human MAIT cells from peripheral blood. These expanded cells exhibit an activated phenotype, cytolytic potential, and enhanced tissue-targeting capabilities. Their functionality as a cancer immunotherapy against solid tumors was evaluated using liver- and pancreatic tumor spheroids.
Results: When engineered to express a T-cell receptor (TCR) specific for the hepatotropic oncovirus HBV, MAIT cells acquired novel antigen specificity and the specific polyfunctionality, while retaining their antimicrobial activity against pathogenic bacteria. Notably, their tumor-homing ability to HBV-associated hepatocellular carcinoma mirrors that of conventional T cells currently used in clinical practice. Furthermore, MAIT cells responded robustly to bacteria isolated from patient-derived pancreatic tumors via activation of 5-OP-RU–specific TCRs. Under hypoxic conditions mimicking the tumor microenvironment, MAIT cells were activated by both experimental infection and bacterial secretomes, leading to a reduction in intratumoral bacterial load within the tumor spheroids. These results highlight a dual function for ex vivo expanded MAIT cells in targeting both tumor-associated bacteria and oncogenic viruses.
Conclusion: Our findings highlight the potential of ex vivo expanded MAIT cells in targeting cancers associated with microbial dysregulation and pave the way for microbiota-targeted immunotherapies.
References
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Swedish Cancer Society. Center for Innovative Medicine. Radiumhemmets forskningsfonder.
[1] MAIT cells
[2] Intratumoral microbiota
[3] Cancer
[4] Immunotherapy
[5] Hepatocellular carcinoma
[6] Pancreatic cancer