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

Williams, Patrick; Basu, Sreyashi; Garcia‐Manero, Guillermo; Hourigan, Christopher S.; Oetjen, Karolyn A.; Cortes, Jorge E.; Ravandi, Farhad; Jabbour, Elias J.; Al‐Hamal, Zainab; Konopleva, Marina; Ning, Jing; Xiao, Lianchun; Hidalgo Lopez, Juliana; Kornblau, Steve M.; Andreeff, Michael; Flores, Wilmer; Bueso‐Ramos, Carlos; Blando, Jorge; Galera, Pallavi; Calvo, Katherine R.; Al‐Atrash, Gheath; Allison, James P.; Kantarjian, Hagop M.; Sharma, Padmanee; Daver, Naval G.

doi:10.1002/cncr.31896

Cited by 330Acute Myeloid Leukemia ResearchCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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

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Williams, Patrick, Basu, Sreyashi, Garcia‐Manero, Guillermo, Hourigan, Christopher S., Oetjen, Karolyn A., Cortes, Jorge E., Ravandi, Farhad, Jabbour, Elias J. +17 more·2019·Cancer

DOI 10.1002/cncr.31896PMC PMC6467779

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Abstract

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.

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TP53 mutant MDS/AML patients have significant upregulation of PDL1 in leukemic stem cells as well as a highly immunosuppressive microenvironment.
“data in TP53 mutant MDS/AML patients with significant upregulation of PDL1 in leukemic stem cells as well as a highly immunosuppressive microenvironment.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML (2025) · cites this paper as [52]
The Results (Figure 5; page unavailable) report more frequent PD-L1-positive blasts in TP53-mutated AML than in non-TP53-mutated AML. The Discussion (page unavailable) also reports more regulatory T cells in AML marrow than in healthy-donor marrow. Neither finding establishes PD-L1 upregulation specifically in leukemic stem cells or a highly immunosuppressive microenvironment specifically in TP53-mutant MDS/AML patients; the study's findings here concern AML, not MDS. (LLM, conf=0.88)
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TP53 Mutations in Acute Myeloid Leukemia: Still a Daunting Challenge?
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Characterization of a Novel FLT3 BiTE Molecule for the Treatment of Acute Myeloid Leukemia
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Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients
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Pathogenic and therapeutic roles of cytokines in acute myeloid leukemia
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An Immune Risk Score Predicts Survival of Patients with Acute Myeloid Leukemia Receiving Chemotherapy
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Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia
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Regulation of hematopoietic and leukemia stem cells by regulatory T cells
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p53 mutation and deletion contribute to tumor immune evasion
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Immune checkpoint inhibitors in acute myeloid leukemia
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Immunotherapeutic strategies beyond the PD-1/PD-L1 pathway in head and neck squamous cell carcinoma – A scoping review on current developments in agents targeting TIM-3, TIGIT, LAG-3, and VISTA
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A multi-arm phase Ib/II study designed for rapid, parallel evaluation of novel immunotherapy combinations in relapsed/refractory acute myeloid leukemia
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A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents
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Antigen-Specific TCR-T Cells for Acute Myeloid Leukemia: State of the Art and Challenges
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“51,52 With targeted agents for mutations that may have one or more significant hot spots, there is an art to further drug development in terms of thoughtful trial design, patient eligibility by target, and applicability of results to varied populations.”
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Treg infiltration and the expression of immune checkpoints associated with T cell exhaustion in AML.
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The expression patterns and prognostic significance of PD-1 and TIM-3 on T cells and the differentiated subsets in acute myeloid leukemia
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Abstract 3205: Defining the immune checkpoint landscape of acute myeloid leukemia (AML)
Daver, N. G., Basu, S., Garcia‐Manero, G., Cortes, J. E., Ravandi, F., Kornblau, S. M., Konopleva, M. Y., Andreeff, M., Borthakur, G. M., Jain, N., et al. (2016) · Cancer Research · doi:10.1158/1538-7445.am2016-3205 · Cited by 7 · see citing works
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Expression of immune checkpoint molecules in Iraqi acute myeloid leukemia patients
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Authors: Williams, P., Basu, S., Garcia‐Manero, G., Hourigan, C. S., Oetjen, K. A., Cortes, J. E., Ravandi, F., Jabbour, E. J., Al‐Hamal, Z., Konopleva, M., Ning, J., Xiao, L., Hidalgo Lopez, J., Kornblau, S. M., Andreeff, M., Flores, W., Bueso‐Ramos, C., Blando, J., Galera, P., Calvo, K. R., Al‐Atrash, G., Allison, J. P., Kantarjian, H. M., Sharma, P., & Daver, N. G.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
National Institutes of Health (US)
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas
Immunotherapy Platform The University of Texas MD Anderson Cancer Center Houston Texas
Department of Hematopathology The University of Texas MD Anderson Cancer Center Houston Texas
Department of Stem Cell Transplant and Cell Therapy The University of Texas MD Anderson Cancer Center Houston Texas
Corresponding author: Sharma, Padmanee
Daver, Naval G.
ORCID: Williams, Patrick
Basu, Sreyashi
Garcia‐Manero, Guillermo
Hourigan, Christopher S.
Oetjen, Karolyn A.
Ravandi, Farhad
Jabbour, Elias J.
Konopleva, Marina
Ning, Jing
Xiao, Lianchun
Kornblau, Steve M.
Andreeff, Michael
Blando, Jorge
Galera, Pallavi
Calvo, Katherine R.
Allison, James P.
Kantarjian, Hagop M.
Sharma, Padmanee
Daver, Naval G.
Venue: Cancer
Publisher: Wiley
Published: 2018-11-30
Volume: 125
Issue: 9
Pages: 1470-1481
ISSN: 0008-543X (ISSN-L)
1097-0142
DOI: 10.1002/cncr.31896
PMC: PMC6467779
OpenAlex: W2903041954
Cited by: 330
References: 49
Citations by year: 2026: 13 · 2025: 39 · 2024: 41 · 2023: 53 · 2022: 47 · 2021: 67 · 2020: 50 · 2019: 20
FWCI: 24.74
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cancer (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA009666, CA016672)
National Institutes of Health (CA100632)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: acute myeloid leukemia, T cell subsets, immune checkpoint receptors, immune checkpoint ligands, bone marrow, regulatory T cells, PD-1, PD-L1, TIM-3, LAG-3, OX40, ICOS, relapsed AML, TP53 mutation, DNA methylation, FLT3, IDH1, IDH2
MeSH terms: Adult, Aged, Bone Marrow, Bone Marrow Cells, Female, Humans, Immunohistochemistry, Ligands, Male, Middle Aged, Phenotype, Receptors, Immunologic, Recurrence, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Case-Control Studies, Immunophenotyping, T-Lymphocyte Subsets, Leukemic Infiltration, Lymphocyte Count, Genes, cdc

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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

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