@article{d151fedc5ca94e33b2ebaaa1e76c9d9a,
title = "Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma",
abstract = "Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. Desmoplastic malignancies, such as cholangiocarcinoma (CCA), have an abundant tumor immune microenvironment (TIME). However, to date, ICB monotherapy in such malignancies has been ineffective. Herein, we identify tumor-associated macrophages (TAMs) as the primary source of programmed death-ligand 1 (PD-L1) in human and murine CCA. In a murine model of CCA, recruited PD-L1+ TAMs facilitated CCA progression. However, TAM blockade failed to decrease tumor progression due to a compensatory emergence of granulocytic myeloid-derived suppressor cells (G-MDSCs) that mediated immune escape by impairing T cell response. Single-cell RNA sequencing (scRNA-Seq) of murine tumor G-MDSCs highlighted a unique ApoE G-MDSC subset enriched with TAM blockade; further analysis of a human scRNA-Seq data set demonstrated the presence of a similar G-MDSC subset in human CCA. Finally, dual inhibition of TAMs and G-MDSCs potentiated ICB. In summary, our findings highlight the therapeutic potential of coupling ICB with immunotherapies targeting immunosuppressive myeloid cells in CCA.",
author = "Emilien Loeuillard and Jingchun Yang and Buckarma, {Eee L.N.} and Juan Wang and Yuanhang Liu and Caitlin Conboy and Pavelko, {Kevin D.} and Ying Li and Daniel O'Brien and Chen Wang and Graham, {Rondell P.} and Smoot, {Rory L.} and Haidong Dong and Sumera Ilyas",
note = "Funding Information: EL was supported by the Cholangiocarcinoma Foundation. EB was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grant T32DK07198. RLS was supported by a Department of Defense Career Development Grant (W81XWH-18-1-0297). HD was supported by the Richard M. Schulze Family Foundation and the Mayo Clinic Center for Individualized Medicine Biomarker Discovery Program for Immunotherapy (IMPRESS). SI was supported by the NIH/National Cancer Institute (1K08CA236874), an American Gastroenterology Association Research Scholar Award, the Mayo Center for Biomedical Discovery, the Mayo Center for Cell Signaling in Gastroenterology (Pilot & Feasibility Award P30DK084567), the Mayo Hepatobiliary Cancer SPORE (P50 CA210964) Career Enhancement Program, the Satter Family Liver Cancer Award, and the Mayo Foundation. This publication was made possible through support by core facilities at the Mayo Clinic, including the Immune Monitoring Core, the Medical Genome Facility Gene Analysis Core, the Pathology Research Core, the Antibody Hybridoma Core, and the X-Ray Imaging Resources Core. Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = oct,
day = "1",
doi = "10.1172/JCI137110",
language = "English (US)",
volume = "130",
pages = "5380--5396",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",
}