Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
In: Journal for ImmunoTherapy of Cancer, Jg. 12 (2024-04-11), Heft 4
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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: | Turpin, Rita ; Liu, Ruixian ; Munne, Pauliina ; Peura, Aino ; Rannikko, Jenna ; Philips, Gino ; Boeckx, Bram ; Salmelin, Natasha ; Hurskainen, Elina ; Suleymanova, Ilida ; Aung, July ; Vuorinen, Elisa ; Lehtinen, Laura ; Mutka, Minna ; Kovanen, Panu ; Niinikoski, Laura ; Meretoja, Tuomo ; Mattson, Johanna ; Mustjoki, Satu ; Saavalainen, Päivi ; Goga, Andrei ; Lambrechts, Diether ; Pouwels, Jeroen ; Hollmén, Maija ; Klefström, Juha |
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Zeitschrift: | Journal for ImmunoTherapy of Cancer, Jg. 12 (2024-04-11), Heft 4 |
Veröffentlichung: | eScholarship, University of California, 2024 |
Medientyp: | academicJournal |
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