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Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
- 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
- et al.
Published Web Location
https://doi.org/10.1136/jitc-2023-008053Abstract
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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