SUMMARY
While 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.
OBJECTIVE
Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that spread to the Caribbean in 2013 and the United States in 2014. CHIKV-infected patients develop inflammatory arthritis that can persist for months to years, but little is known about the rheumatologic and immunologic features of CHIKV arthritis in humans, particularly as compared to rheumatoid arthritis (RA). Here, we describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.
METHODS
Patients were assessed by history, physical examination, and laboratory studies. All patients with CHIKV arthritis had detectable anti-CHIKV IgG. Using cytometry by time of flight (CyTOF), we analyzed peripheral blood mononuclear cells in CHIKV-infected patients, healthy controls, and patients with untreated, active RA.
RESULTS
Among ten CHIKV-infected individuals, eight developed persistent symmetric polyarthritis, who otherwise met the 2010 ACR/EULAR criteria for (seronegative) RA. CyTOF analysis revealed that RA and CHIKV-infected patients had greater percentages of activated and effector CD4+ and CD8+ T cells than healthy controls.
CONCLUSION
In addition to similar clinical features, patients with CHIKV infection and RA develop highly similar peripheral T cell phenotypes. These overlapping clinical and immunologic features highlight a need for rheumatologists to consider CHIKV infection when evaluating patients with new, symmetric polyarthritis.
Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a common phenomenon of JAK2 hyperactivation. JAK2 has the potential to activate multiple other signaling molecules, either directly through downstream effectors, or indirectly through induction of target gene expression. We have interrogated myeloproliferative signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) patient samples using mass cytometry, which allows the quantitative measurement of multiple signaling molecules simultaneously at the single cell level, in cell populations representing a nearly complete spectrum of hematopoiesis. MF and sAML malignant cells demonstrated a high prevalence of hyperactivation of the JAK-STAT, MAP kinase, PI3 kinase, and NFκB signaling pathways. Constitutive NFκB signaling was evident across MF and sAML patients. A supporting GSEA analysis of MF showed many NFκB target genes to be expressed above normal levels in MF patient CD34+ cells. NFκB inhibition suppressed colony formation from MF CD34+ cells. This study indicates that NFκB signaling contributes to human myeloproliferative disease and is abnormally activated in MF and sAML.
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