PT  - JOURNAL ARTICLE
AU  - Turpin, Rita
AU  - Liu, Ruixian
AU  - Munne, Pauliina M
AU  - Peura, Aino
AU  - Rannikko, Jenna H
AU  - Philips, Gino
AU  - Boeckx, Bram
AU  - Salmelin, Natasha
AU  - Hurskainen, Elina
AU  - Suleymanova, Ilida
AU  - Aung, July
AU  - Vuorinen, Elisa M
AU  - Lehtinen, Laura
AU  - Mutka, Minna
AU  - Kovanen, Panu E
AU  - Niinikoski, Laura
AU  - Meretoja, Tuomo J
AU  - Mattson, Johanna
AU  - Mustjoki, Satu
AU  - Saavalainen, Päivi
AU  - Goga, Andrei
AU  - Lambrechts, Diether
AU  - Pouwels, Jeroen
AU  - Hollmén, Maija
AU  - Klefström, Juha
TI  - Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment
AID  - 10.1136/jitc-2023-008053
DP  - 2024 Apr 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e008053
VI  - 12
IP  - 4
4099  - http://jitc.bmj.com/content/12/4/e008053.short
4100  - http://jitc.bmj.com/content/12/4/e008053.full
SO  - J Immunother Cancer2024 Apr 01; 12
AB  - 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.Data are available upon reasonable request.