@article{2adcc033200f4e209feae966ebe73e50,
title = "High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy",
abstract = "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 IFNγ. 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. Comprehensive changes in the tumor microenvironment during successful immune-checkpoint therapy are profiled, implicating a key role for polarization of infiltrating macrophages in the anti-tumor immune milieu.",
author = "Gubin, {Matthew M.} and Ekaterina Esaulova and Ward, {Jeffrey P.} and Malkova, {Olga N.} and Daniele Runci and Pamela Wong and Takuro Noguchi and Arthur, {Cora D.} and Wei Meng and Elise Alspach and Medrano, {Ruan F.V.} and Catrina Fronick and Michael Fehlings and Newell, {Evan W.} and Fulton, {Robert S.} and Sheehan, {Kathleen C.F.} and Oh, {Stephen T.} and Schreiber, {Robert D.} and Artyomov, {Maxim N.}",
note = "Funding Information: The authors thank all members of the Schreiber and Artyomov labs for helpful discussions and technical support. We especially thank K. Zaitsev (Artyomov lab) for computational discussions. We thank the staff at ITMO University for assistance with the graphical abstract. We thank E. Unanue and G. Randolph (Washington University) for helpful comments and criticisms. We would also like to thank L. Yang and C. Wilson for assistance with MHC multimer development and staining. We thank E. Lantelme and D. Brinja at the Flow Cytometry Core for technical support with flow cytometry cell sorting. This work was supported by grants to R.D.S. and subcontract to E.W.N. from the National Cancer Institute of the National Institutes of Health under award number RO1CA190700 . This work was also supported by grants to R.D.S. from the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, Janssen Pharmaceutical Company of Johnson and Johnson, and the Prostate Cancer Foundation and by a Stand Up To Cancer–Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.M.G. was supported by a postdoctoral training grant (Irvington Postdoctoral Fellowship) from the Cancer Research Institute. E.E. is partially supported by a grant (08-08) from the Government of Russian Federation. J.P.W. is supported by the National Cancer Institute of the National Institutes of Health Paul Calabresi Career Development Award in Clinical Oncology ( K12CA167540 ). Aspects of studies including mass cytometry were performed with assistance by the Immunomonitoring Laboratory (IML), which is supported by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs and the Alvin J. Siteman Comprehensive Cancer Center that, in turn, is supported by National Cancer Institute of the National Institutes of Health Cancer Center Support Grant under award number P30CA91842 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = nov,
day = "1",
doi = "10.1016/j.cell.2018.09.030",
language = "English (US)",
volume = "175",
pages = "1014--1030.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}