RT Journal Article
SR Electronic
T1 Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e008053
DO 10.1136/jitc-2023-008053
VO 12
IS 4
A1 Turpin, Rita
A1 Liu, Ruixian
A1 Munne, Pauliina M
A1 Peura, Aino
A1 Rannikko, Jenna H
A1 Philips, Gino
A1 Boeckx, Bram
A1 Salmelin, Natasha
A1 Hurskainen, Elina
A1 Suleymanova, Ilida
A1 Aung, July
A1 Vuorinen, Elisa M
A1 Lehtinen, Laura
A1 Mutka, Minna
A1 Kovanen, Panu E
A1 Niinikoski, Laura
A1 Meretoja, Tuomo J
A1 Mattson, Johanna
A1 Mustjoki, Satu
A1 Saavalainen, Päivi
A1 Goga, Andrei
A1 Lambrechts, Diether
A1 Pouwels, Jeroen
A1 Hollmén, Maija
A1 Klefström, Juha
YR 2024
UL http://jitc.bmj.com/content/12/4/e008053.abstract
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.