Liver-specific programming of myeloid cells promotes intrahepatic immunosuppression

• DOI: 10.4049/jimmunol.200.supp.46.13
• Publication Date: 2023-01-01T11:16:46Z
• Authors: Prajna Guha; Jillian Gardell; Mikayla Lopes; N Joseph Espat; Steven C Katz
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

Abstract Liver is a tolerogenic organ and has variety of immune cells resulting in a profoundly immunosuppressive space. We recently reported that GM-CSF/JAK2/STAT3 axis drives liver myeloid suppressor cell (L-MDSC) proliferation and STAT3 inhibition causes activation of apoptosis signaling via Bax up-regulation. Herein, we explore liver specific programming events that promote L-MDSC suppressive conditioning. Bone marrow derived MDSC (BM-MDSC) were expanded in CD45.1+ mice in response to intraperitoneal MC38 tumors. CD45.1+ BM-MDSC were adoptively transferred into CD45.2+ recipient mice via tail vein (TV) or portal vein (PV). CD11b+ cells were harvested 48 hrs later from recipient liver and lungs. Liver from PV and lung from TV CD45.1+ MDSC recipients were compared. There was increased expansion of CD45.1+ MDSC (CD11b+Gr1+) in PV-liver as compared to TV-lung group (Liver-PV 45±3% vs. Lung-TV 15±2% vs. Tumor 43±3, p<0.001, n=5) with increased numbers of the more immunosuppressive monocytic MDSC (M-MDSC) subtype in CD45.1+ transferred cells in liver as compared to lung (Liver-PV 61±4%, Lung-TV 40±3%, Tumor 58±3 p<0.005, n=5). Enhanced pSTAT3 expression (mediator of MDSC expansion) in CD45.1+CD11b+Gr1+ cells in liver was observed as compared to lung (pSTAT3: Liver-PV 54±4, Lung-TV 30±5, p<0.05 n=5). Quantitative PCR of MDSCs isolated from Liver-PV showed significantly decreased levels (8.5 fold, p<0.05, n=4) of pro-apoptotic Bax protein as compared to Lung-TV indicating MDSC apoptosis resistance following conditioning in the liver. These data indicate that L-MDSCs are directed towards suppressive programming and blocking STAT3 may have clinical application for enhancing the efficacy of immunotherapy for liver tumors.