The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia.

BACKGROUND: Phenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking. METHODS: T-cell infiltration was quantified on BM biopsies from 13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 [PD1], cytotoxic T-lymphocyte antigen 4 [CTLA4], lymphocyte-activation gene 3 [LAG3], T-cell immunoglobulin and mucin-domain containing-3 [TIM3]) and stimulatory receptors (glucocorticoid-induced tumor necrosis factor receptor-related protein [GITR], OX40, 41BB [a type 2 transmembrane glycoprotein receptor], inducible T-cell costimulatory [ICOS]) on T-cell subsets and the expression of their ligands (41BBL, B7-1, B7-2, ICOSL, PD-L1, PD-L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next-generation sequencing for 28 myeloid-associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1[IDH1], IDH2, Tet methylcytosine dioxygenase 2 [TET2], and Fms-related tyrosine kinase 3 [FLT3]). RESULTS: On histochemistry evaluation, the T-cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T-regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1-positive/OX40-positive T cells were more frequent in AML BMAs, and a higher frequency of PD1-positive/cluster of differentiation 8 (CD8)-positive T cells coexpressed TIM3 or LAG3. PD1-positive/CD8-positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53-mutated AML were more frequently positive for PD-L1. CONCLUSIONS: The preserved T-cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T-cell-harnessing therapies in AML.

Improving the detection of patients with inherited predispositions to hematologic malignancies using next-generation sequencing-based leukemia prognostication panels.

Recognizing and referring patients with possible inherited cancer predisposition syndromes for appropriate genetic evaluation and testing provides insights into optimal patient treatment approaches and also can provide education and testing opportunities for family members. Next-generation sequencing (NGS)-based, targeted genotyping for somatic mutations is increasingly used in the diagnosis, prognostication, and treatment selection for patients with hematologic malignancies. However, certain mutations that may be somatically acquired can also be present as germline mutations in some individuals and families. Whether the results of NGS-based leukemia panels can be used to inform decisions and subsequent evaluation of patients with possible inherited cancer predispositions has not been described previously. Because a normal control often is not available when using NGS panels in patients with hematologic malignancies, NGS panel results offer both an opportunity and a challenge to determine the origin and pathogenicity of identified mutations. In the absence of a matched germline control, variant allele frequency (VAF) estimation and data from publically available data sets provide important clues to the possible germline origin of a variant. Careful annotation and review of NGS panels in patients with hematologic malignancies can provide a useful screening tool to systematically improve upon the detection of potentially pathogenic germline variants. Cancer 2018;124:2704-2713. © 2018 American Cancer Society.