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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1470-1481
Number of pages12
JournalCancer
Volume125
Issue number9
DOIs
StatePublished - May 1 2019
Externally publishedYes

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T-Lymphocyte Subsets
Acute Myeloid Leukemia
Ligands
T-Lymphocytes
Bone Marrow
Mucins
Regulatory T-Lymphocytes
Lymphocyte Activation
Programmed Cell Death 1 Receptor
Costimulatory and Inhibitory T-Cell Receptors
CD80 Antigens
Protein Methyltransferases
Tissue Donors
CTLA-4 Antigen
Isocitrate Dehydrogenase
Dioxygenases
Tumor Necrosis Factor Receptors
p53 Genes
Glucocorticoid Receptors
DNA Methylation

Keywords

  • acute myeloid leukemia
  • flow cytometry
  • immune checkpoint
  • immunotherapy
  • T cell

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.

In: Cancer, Vol. 125, No. 9, 01.05.2019, p. 1470-1481.

Research output: Contribution to journalArticle

Williams, P, Basu, S, Garcia-Manero, G, Hourigan, CS, Oetjen, KA, Cortes, JE, Ravandi, F, Jabbour, EJ, Al-Hamal, Z, Konopleva, M, Ning, J, Xiao, L, Hidalgo Lopez, J, Kornblau, SM, Andreeff, M, Flores, W, Bueso-Ramos, C, Blando, J, Galera, P, Calvo, KR, Al-Atrash, G, Allison, JP, Kantarjian, HM, Sharma, P & Daver, NG 2019, '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', Cancer, vol. 125, no. 9, pp. 1470-1481. https://doi.org/10.1002/cncr.31896
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. / 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. In: Cancer. 2019 ; Vol. 125, No. 9. pp. 1470-1481.
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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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TY - JOUR

T1 - 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

AU - Williams, Patrick

AU - Basu, Sreyashi

AU - Garcia-Manero, Guillermo

AU - Hourigan, Christopher S.

AU - Oetjen, Karolyn A.

AU - Cortes, Jorge E.

AU - Ravandi, Farhad

AU - Jabbour, Elias J.

AU - Al-Hamal, Zainab

AU - Konopleva, Marina

AU - Ning, Jing

AU - Xiao, Lianchun

AU - Hidalgo Lopez, Juliana

AU - Kornblau, Steve M.

AU - Andreeff, Michael

AU - Flores, Wilmer

AU - Bueso-Ramos, Carlos

AU - Blando, Jorge

AU - Galera, Pallavi

AU - Calvo, Katherine R.

AU - Al-Atrash, Gheath

AU - Allison, James P.

AU - Kantarjian, Hagop M.

AU - Sharma, Padmanee

AU - Daver, Naval G.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

KW - acute myeloid leukemia

KW - flow cytometry

KW - immune checkpoint

KW - immunotherapy

KW - T cell

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