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High Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune Checkpoint Cancer Therapy
Gubin MM, Esaulova E, Ward JP, Malkova ON, Runci D, Wong P, Noguchi T, Arthur CD, Meng W, Alspach E, Medrano RV, Fronick C, Fehlings M, Newell EW, Fulton RS, Sheehan KF, Oh ST, Schreiber RD, Artyomov MN
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.