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Comprehensive characterization of VISTA expression in patients with acute myeloid leukemia

Lamble, A., Kosaka, Y., Huang, F. et al.

Background:
Acute myeloid leukemia (AML) is a candidate for novel therapeutics, specifically immune checkpoint (IC) inhibitors. V-domain Ig Suppressor of T cell Activation (VISTA) is a novel IC previously shown to be present on hematologic cells and inhibitory towards T cells. VISTA’s role within AML has yet to be defined. We performed detailed studies to characterize VISTA expression of lymphoid cell subsets in patients with AML. Additionally, we assessed the impact of VISTA blockade on the functional capacity of T cells resident in AML bone marrow.

Methods:
Immunophenotyping was performed on mononuclear cells from primary AML patient specimens using mass cytometry (CyTOF) by staining samples with two panels containing 32 antibodies to surface markers and cytokines. T cells, and their subsets (naïve, central memory, effector memory, effector memory CD45RA+, T regulatory) were defined by the presence or absence of specific surface markers. Functional assays measured both the proliferative capacity and cytokine production profile of bone marrow T cells in response to CD3 stimulation and VISTA blockade in the context of the tumor microenvironment.

Results:
10 bone marrow samples from patients with newly diagnosed AML were compared to 5 bone marrow samples from healthy donors. Proportion of T cells and their subsets were similar between patient groups, except T regulatory cells, which represented a higher percentage of mononuclear cells in patients with AML. A higher percentage of T cells within the AML samples expressed VISTA when compared to the healthy donor samples (26% vs 11%, p < 0.05). A higher percentage of AML blasts expressed VISTA when compared to other checkpoint receptor ligands (CD80, CD86, and PD-L1). In both patients with AML and healthy donors, there was minimal proliferation and cytokine production in the setting of VISTA blockade. One patient with AML produced marked elevations of both GM-CSF and M-CSF with VISTA blockade.

Conclusions:
More T cells express VISTA in patients with AML than healthy donors. VISTA is more highly expressed on AML blasts than other checkpoint ligands. VISTA blockade does not appear to alter T cell proliferation but can affect cytokine production in a subset of patients.

Citation

Lamble, A., Kosaka, Y., Huang, F. et al. "Comprehensive characterization of VISTA expression in patients with acute myeloid leukemia" Journal of Clinical Oncology (2016): e14546