High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy

Matthew M. Gubin, Ekaterina Esaulova, Jeffrey P. Ward, Olga N. Malkova, Daniele Runci, Pamela Wong, Takuro Noguchi, Cora D. Arthur, Wei Meng, Elise Alspach, Ruan F.V. Medrano, Catrina Fronick, Michael Fehlings, Evan W. Newell, Robert Fulton, Kathleen Sheehan, Stephen Oh, Robert Schreiber, Maksym Artomov

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50 Scopus citations

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.

Original languageEnglish
Pages (from-to)1014-1030.e19
JournalCell
Volume175
Issue number4
DOIs
StatePublished - Nov 1 2018

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    Gubin, M. M., Esaulova, E., Ward, J. P., Malkova, O. N., Runci, D., Wong, P., Noguchi, T., Arthur, C. D., Meng, W., Alspach, E., Medrano, R. F. V., Fronick, C., Fehlings, M., Newell, E. W., Fulton, R., Sheehan, K., Oh, S., Schreiber, R., & Artomov, M. (2018). High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy. Cell, 175(4), 1014-1030.e19. https://doi.org/10.1016/j.cell.2018.09.030