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

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.

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

“…Only a more recent study has reported phenotypic characterization of immune cells in the BM of patients with AML. The authors found that PD1 + /OX40 + T cells were more frequent in the BM of patients with AML, and there was a higher frequency of PD1 + CD8 + T cells coexpressed with Tim‐3 or LAG‐3 . In this study, we further investigated the frequency of CTLA‐4 and LAG‐3 coexpression with CD244 and CD57, which are common markers for evaluating T‐cell exhaustion and the immunosenescence of CD3 + , CD4 + and CD8 + T cells …”

A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

“…Further investigation of the function of these PD‐1+Vβ+ T cells in AML and their association with disease relapse is needed. Moreover, it would be worthy to combine the detection of PD‐L1 expression in AML cells, which may be an important predicted marker for immunotherapy …”

“…However, unlike B‐cell leukemia and lymphoma, the application of immunotherapy for acute myeloid leukemia (AML) has been limited due to limited understanding of global T cell immune dysfunction in AML . Multiple aspects of T cell dysfunction including lower activation, terminal proliferation, exhaustion, and senescence are functioning in AML at diagnosis, and impairment of T cell function might be mediated by up‐regulating immune checkpoint receptors, such as programmed death‐1 (PD‐1), lymphocyte‐activation gene 3, T‐cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3) . For example, CD8+ T cell dysfunction in AML was in part reversible upon PD‐1 blockade in vitro, and PD‐1 blockade could enhance CD33‐CD3 BiTE antibody construct‐mediated cytotoxicity in AML .…”

Will deeper characterization of the landscape of immune checkpoint molecules in acute myeloid leukemia bone marrow lead to improved therapeutic targeting?

“…Recently, studies characterizing T‐cell dysfunction and the cells’ reversibility with intensive chemotherapy in patients with AML have been published, but a detailed understanding of the dynamic and serial changes in the immune checkpoint molecules is lacking . In this issue of Cancer , Williams et al, in an exhaustive manner, explored the bone marrow microenvironment including, but not limited to, PD‐L1 expression and the quantity of infiltrated T cells . They assessed the T‐cell quantity in healthy versus AML bone marrow and demonstrated the expression pattern of a set of targetable coinhibitory and costimulatory receptors on T cells, and their respective ligands on the AML blasts, using multicolor flow cytometry …”

“…In this issue of Cancer , Williams et al, in an exhaustive manner, explored the bone marrow microenvironment including, but not limited to, PD‐L1 expression and the quantity of infiltrated T cells . They assessed the T‐cell quantity in healthy versus AML bone marrow and demonstrated the expression pattern of a set of targetable coinhibitory and costimulatory receptors on T cells, and their respective ligands on the AML blasts, using multicolor flow cytometry …”