Introduction
Acute myeloid leukemia (AML) is a fast-growing malignant hematological disease that occurs in large, immature white blood cells [
1]. The immune systems of patients with AML become uncontrolled, leading to leukemia that cannot develop normal-functioning blood cells. Although treatments for curing AML, such as chemotherapy and hematopoietic stem cell transplantation (HSCT), have appeared in recent years, the outcome of some patients who are unable to undergo intensive chemotherapy and HSCT remains dismal with a poor survival of only 5 to 10 months [
2,
3]. Therefore, novel strategies such as cellular immunotherapy have been proposed and increasingly investigated.
In the past decade, there have been numerous efforts toward developing specific T cell-based immunotherapies to manage cancer [
4‐
6]. γδ T cells are a T cell subset that comprise approximately 5–10 % of all peripheral T cells in healthy individuals [
7]. Due to the antitumor function of γδ T cells, they have been proposed to have therapeutic potential for cancer treatment [
8‐
10]. Several in vivo and in vitro data have demonstrated that γδ T cells are excellent candidates for further improving immunotherapy efficacy because of their intrinsic characteristics and function [
11,
12]. Accumulating evidence supports a particular antitumor cytotoxicity value for γδ T cells in the development of immunotherapy-based approaches for hematological malignancies such as myelodysplastic syndromes (MDS), multiple myeloma (MM), and chronic myeloid leukemia (CML) [
13‐
15]. Despite encouraging preclinical studies of some hematological malignancies, γδ T cell-based immunotherapy for AML patients remains in its infancy, and the immune characteristics of γδ T cells in AML require further elucidation.
Recent insights into the structure of the γδ T cell receptor (TCR) and its ligands strongly indicate that γδ T cells possess unique functions for defending hosts against an extensive range of infections and stresses [
7,
10,
16]. A growing body of evidence demonstrates that γδ T cells can act as functional agents for immune defense against tumors or pathogenic invaders in inflammatory reactions; they perform different functions based on their tissue distribution, antigen–receptor structure, and local microenvironment [
17]. Recently, it has been reported that the phenotype and distribution of γδ T cells in human breast cancer might serve as a prognostic factor predicting clinical outcome [
18]. Our previous study reported that clonally expanded
TRDV4 T cells might lead to relatively better outcome for patients diagnosed with T – cell acute lymphoblastic leukemia (T-ALL) after HSCT [
19]. However, little is known about the correlation between γδ T cells and AML outcome. In this study, we analyze the distribution and clonality of
TRDV subfamilies in γδ T cells sorted from the peripheral blood (PB) and discuss the clinical relevance of γδ T cell subfamilies in AML patients.
Discussion
Although treatments for curing AML have appeared in recent years, the clinical outcomes of some AML patients have not been positive. Recent studies have suggested that there were restricted distribution and clonality for the
TRDV subfamilies in different diseases including immune thrombocytopenic purpura, B cell non-Hodgkin lymphoma, allergic rhinitis, MDS, CML, and graft versus host disease (GVHD) [
20‐
25]. Understanding the mechanisms underlying the γδ T cell immune response in patients with leukemia is vital for developing strategies for leukemia immunotherapy [
26‐
28]. To investigate the immune characteristics of γδ T cells in patients with AML, we first sorted the γδ T cells from the PB of AML patients and analyzed their TCR
Vδ repertoire. We then attempted to characterize the correlation between oligoclonal expansion of TCR
Vδ repertoire and clinical outcome.
In PB T cells from healthy individuals, the
TRDV repertoire expression pattern is unrestricted. In contrast, we found significantly restricted
TRDV subfamily expression in the γδ T cells from patients with AML. Such an alteration in the
TRDV repertoire distribution in AML appeared to be different for different diseases, e.g., the most frequently expressed
TRDV genes were
TRDV1 and
TRDV2 followed by
TRDV8 and
TRDV3 in MDS patients [
22]. This observation suggests that different subfamilies of γδ T cells might be preferentially active in different diseases and different immune statuses for patients with the same disease.
In immunodeficient patients with leukemia, it is difficult to distinguish the role of oligoclonal T cells, which may serve as reactive T cell clones directed against leukemia. In contrast, there may be clonal absence because T cell proliferation is suppressed by different factors in leukemia. For example,
TRDV2 T cells are reduced and dysfunctional in some MDS patients [
15,
19,
29]. To further investigate the role of oligoclonal
TRDV T cells in AML patients, we first analyzed the correlation between clonally expanded
TRDV T cells and clinical outcome. We found that different oligoclonal
TRDV subfamily T cells might have unique functions. We found that the clonal expansion patterns of
TRDV4 and
TRDV8 T cells might be independent protective factors for CR, which is consistent with our previous findings in which we found that clonally expanded
TRDV4 T cells might be related to better outcome for a T-ALL patient [
19]. We suggested that such expanded
TRDV4 and
TRDV8 T cell clones might be reactive T cell clones directed against leukemia that serve as biomarkers for the therapeutic efficacy of AML patients. However, a higher frequency of clonally expanded
TRDV8 was also found in MDS patients who developed AML [
22]. Thus, further investigation is needed to characterize the function of
TRDV8 T cell clones in vitro and in vivo. Interestingly, we also found that
TRDV5 and
TRDV6 T cells might be related to AML recurrence. These oligoclonal
TRDV5 and
TRDV6 T cells might be indicators of minimal residual disease in AML patients. However, this hypothesis requires confirmation with a larger cohort.
In conclusion, to the best of our knowledge, this is the first attempt to analyze the distribution and clonality of the TRDV repertoire in γδ T cells in AML patients. Alterations in the peripheral TRDV gene repertoire are an important characteristic of γδ T cells in AML patients, which may be related to the immune response, antileukemia effects, and patient outcome. These findings might provide new data regarding the characteristics of cellular immunity in AML patients. The oligoclonal expansion of TCR Vδ T cells may serve not only as an immune biomarker for clinical outcome but also as an antileukemia immune status indicator in AML patients. Based on this study, we will further investigate the function of the TCR Vδ T cells subfamilies in co-culture models and mouse xenograft model.
Acknowledgements
Not applicable.