Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment
In: Journal for ImmunoTherapy of Cancer, Jg. 12 (2024-04-01), Heft 4
Online
academicJournal
Zugriff:
Background Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.Methods Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity.Results We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity.Conclusions Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.
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Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment
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Autor/in / Beteiligte Person: | Tuomo J Meretoja ; Liu, Ruixian ; Lambrechts, Diether ; Mattson, Johanna ; Mustjoki, Satu ; Saavalainen, Päivi ; Boeckx, Bram ; Hollmen, Maija ; Turpin, Rita ; Pauliina M Munne ; Peura, Aino ; Jenna H Rannikko ; Philips, Gino ; Salmelin, Natasha ; Hurskainen, Elina ; Suleymanova, Ilida ; Aung, July ; Elisa M Vuorinen ; Lehtinen, Laura ; Mutka, Minna ; Panu E Kovanen ; Niinikoski, Laura ; Goga, Andrei ; Pouwels, Jeroen ; Klefström, Juha |
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Zeitschrift: | Journal for ImmunoTherapy of Cancer, Jg. 12 (2024-04-01), Heft 4 |
Veröffentlichung: | BMJ Publishing Group, 2024 |
Medientyp: | academicJournal |
ISSN: | 2051-1426 (print) |
DOI: | 10.1136/jitc-2023-008053 |
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