American Association for Cancer Research
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FIGURE 4 from Single-Cell CD4 and CD8 T-Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy

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posted on 2024-03-06, 14:20 authored by Jessica L. Root, Poonam N. Desai, Christopher Ly, Bofei Wang, Fatima Zahra Jelloul, Jing Zhou, Sean Mackay, Mansour Alfayez, Jairo Matthews, Sherry Pierce, Patrick K. Reville, Naval Daver, Hussein A. Abbas

Single-cell analysis of IsoPlexis data for CD4 cells (left) and CD8 cells (right). A, UMAP visualization colored by sample location (orange for PB, purple for BM). B, UMAP colored by time point (green for baseline, pink for post-therapy). C, Neighborhood graph depicting differential abundance testing results obtained from miloR. Colors represent the log fold-change between baseline (red) and post-IO (blue) cells. White neighborhoods are nondifferential (FDR 10%). The edges depict links between cells shared by neighborhoods. D, Beeswarm plot of the distribution of neighborhoods by timepoint. E, Beeswarm plot of the distribution of neighborhoods by UMAP-based cluster.

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ARTICLE ABSTRACT

Acute myeloid leukemia (AML) is a heterogeneous malignancy of the blood primarily treated with intensive chemotherapy. The allogeneic T-cell antileukemic activity via donor lymphocyte infusions and stem cell transplantation suggests a potential role for checkpoint blockade therapy in AML. While clinical trials employing these treatments have fallen short of expected results, a deeper exploration into the functional states of T cells in AML could bridge this knowledge gap. In this study, we analyzed the polyfunctional activity of T cells in a cohort of patients with relapsed/refractory (RelRef) AML treated on the clinical trial (ClinicalTrials.gov identifier: NCT02397720) of combination therapy using azacitidine and nivolumab (Aza/Nivo). We utilized the single-cell polyfunctional multiplexed immune assay IsoPlexis to evaluate the CD4 and CD8 T cells in peripheral blood and bone marrow samples collected before and after immunotherapy. This revealed at a pseudobulk level that the CD4 T cells exhibited higher functional activity post-immunotherapy (post-IO), suggesting that CD4-directed therapies may play a role in RelRef AML. Additional single-cell analysis revealed significant differences in baseline polyfunctionality in bone marrows of responders as compared with nonresponders for both CD4 and CD8 T cells. Overall, this study highlights the impact of polyfunctional assessment in understanding CD4 and CD8 dynamics in contexts of therapy in AML. We found T-cell polyfunctionality differs between local and systemic microenvironments. Enhanced variability in proteomic profiles of bone marrow CD4 T cells post-IO suggests their pivotal role in AML treatment response. Single-cell analysis identified novel CD4 and CD8 T-cell functional groups linked to immunotherapy response within the bone marrow.