Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy - PubMed (original) (raw)

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Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy

Allison R Greenplate et al. Cancer Immunol Res. 2016 Jun.

Abstract

Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474-80. ©2016 AACR.

©2016 American Association for Cancer Research.

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Figures

Figure 1

Figure 1. Clinical Imaging and Blood Counts

A) Pre-therapy and post-therapy PET/CT scans are shown that highlight a lingular metastasis that increases in size during the course of therapy. B) Select peripheral blood counts and blast cells by manual differential are shown prior to and during therapy. The patient had a pre-existing thrombocytopenia (green line) that worsened over time. After therapy initiation, blasts (yellow) are seen to increase as hemoglobin (Hgb, orange line) drops and white blood cells (blue line, same scale as Hgb) remain in the normal range. As of 9 months post therapy initiation, the patient remains on anti–PD-1 therapy.

Figure 2

Figure 2. Identification of peripheral blasts by mass cytometry in a melanoma patient undergoing anti–PD-1 therapy

A 33 parameter mass cytometry panel was used to immunophenotype peripheral blood from a melanoma patient over the course of anti–PD-1 therapy. A) Cells positive for nucleic acid intercalator, a marker of nuclear DNA, and low for CD45 were identified over the course of therapy, but not in a healthy donor. B) The majority of CD45lo events (blue gate) from the patient expressed intermediate levels of CD33 and high levels of both HLA-DR and CD38 compared to non-blasts, consistent with peripheral myeloblast phenotype. C) Peripheral blasts increased from 1.16% to 4.65% of all PBMC (left). The percentage of T (light blue), B (yellow), and NK (red) cells declined over the course of therapy while the percentage of myeloid cells (green) increased (right).

Figure 3

Figure 3. Frequency of PD-1+ monocytes in this case remained higher during therapy than in untreated healthy controls

A) The percentage of PD-1+ cells was determined for blasts, CD8 T cells, CD4 T cells, myeloid cells, NK cells, and B cells. For healthy, n = 5. B) Biaxial plots show the increase of activated monocytes through dual expression of CD45RA and HLA-DR on non-lymphoid cells from a healthy donor and from the patient over the course of anti–PD-1 therapy.

Figure 4

Figure 4. Peripheral blast phenotype shifts dramatically over the course of anti–PD-1 therapy

A) CD45lo events from the patient were gated and used to create a viSNE map. Blue gates identify major islands of cell density over all four time points. Each population denoted by the letter P followed by a number. B) Increase in cell density within each population (P, right) is shown as fold change over percentage of cells within sectors from the pre-therapy sample (left). C) A heatmap displays intensities of 28 measured proteins for each population identified on the viSNE map. Intensity is shown as heat, calculated as a transformed ratio of medians by the table's minimum.

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