부산대학교 도서관

Byline: Matthew M. Gubin (1,2,9), Ekaterina Esaulova (1,3,9), Jeffrey P. Ward (1,2,4,9), Olga N. Malkova (2), Daniele Runci (1,2), Pamela Wong (1), Takuro Noguchi (5), Cora D. Arthur (1,2), Wei Meng (1,2), Elise Alspach (1,2), Ruan F.V. Medrano (1,2), Catrina Fronick (6), Michael Fehlings (7), Evan W. Newell (7), Robert S. Fulton (6), Kathleen C.F. Sheehan (1,2), Stephen T. Oh (2,8), Robert D. Schreiber [rdschreiber@wustl.edu] (1,2,10,*), Maxim N. Artyomov [martyomov@wustl.edu] (1,**) Highlights * High-dimensional analyses of successful ICT in tumor-bearing mice * ICT induces changes in intratumoral myeloid and lymphoid cells * Tumor-associated monocytes/macrophages display complex cytokine-driven phenotypes * Different cytokines act on tumor-infiltrating monocytes to drive macrophage polarization Summary Although current immune-checkpoint therapy (ICT) mainly targets lymphoid cells, it is associated with a broader remodeling of the tumor micro-environment. Here, using complementary forms of high-dimensional profiling, we define differences across all hematopoietic cells from syngeneic mouse tumors during unrestrained tumor growth or effective ICT. Unbiased assessment of gene expression of tumor-infiltrating cells by single-cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages, distinguishable by the markers CD206, CX3CR1, CD1d, and iNOS, that change over time during ICT in a manner partially dependent on IFN[gamma]. Our data support the hypothesis that this macrophage polarization/activation results from effects on circulatory monocytes and early macrophages entering tumors, rather than on pre-polarized mature intratumoral macrophages. Author Affiliation: (1) Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA (2) The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA (3) Computer Technologies Department, ITMO University, Saint Petersburg, 197110, Russia (4) Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA (5) Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine 3-1-1 Asahi, Matsumoto Nagano, 390-8621, Japan (6) McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St. Louis, MO 63108, USA (7) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore (8) Division of Hematology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8125, St. Louis, MO 63110, USA * Corresponding author Article History: Received 2 January 2018; Revised 13 July 2018; Accepted 13 September 2018 (miscellaneous) Published: October 18, 2018; corrected online: October 26, 2018 (footnote)9 These authors contributed equally (footnote)10 Lead Contact