1. Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
- Author
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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, and Klefström, Juha
- Subjects
Breast Neoplasms ,Dendritic Cells ,Drug Evaluation ,Preclinical ,Immunity ,Innate ,Immunomodulation ,Humans ,Female ,Electron Transport Complex I ,Antineoplastic Agents ,Breast Neoplasms ,Dendritic Cells ,Metformin ,Tumor Microenvironment ,Sulfonamides ,Bridged Bicyclo Compounds ,Heterocyclic - Abstract
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.
- Published
- 2024