Abstract
Aberrant T-cell function is implicated in the pathogenesis of myelodysplastic syndrome (MDS). Monitoring the T-cell receptor (TCR) repertoire can provide insights into T-cell adaptive immunity. Previous studies found skewed TCR repertoires in MDS compared to healthy patients; however these studies that leverage mRNA-based spectratyping have limitations. Furthermore, evaluating the TCR repertoire in context of hypomethylating agents (HMAs) treatment can provide insights into the dynamics of T-cell mediated responses in MDS. We conducted immunosequencing of the CDR3 regions of TCRβ chains in bone marrows of 11 MDS patients prior to treatment (n=11 bone marrows prior to treatment), and in at least 2 timepoints for each patient following treatment (n=26 bone marrow aspirates post-treatment) with (HMA), alongside analyzing bone marrows from 4 healthy donors as controls. TCR repertoires in MDS patients were more clonal and less diverse than healthy donors. However, unlike previous reports, we did not observe significant skewness in CDR3 length or spectratyping. The global metrics of TCR profiling including richness, clonality, overlaps were not significantly changed in responders or non-responders following treatment with HMAs. However, we found an emergence of novel clonotypes in MDS patients who responded to treatment, while non-responders had a higher frequency of contracted clonotypes following treatment. By applying GLIPH2 for antigen prediction, we found rare TCR specificity clusters shared by TCR clonotypes from different patients at pre- or following treatment. Our data show clear differences in TCR repertoires of MDS compared with healthy patients and that novel TCR clonotype emergence in response to HMA therapy was correlated with response. This suggests that response to HMA therapy may be partially driven by T-cell mediated immunity and that the immune-based therapies, which target the adaptive immune system, may play a significant role in select patients with MDS.
Highlights
Myelodysplastic syndrome (MDS) is a clonal hematologic disorder characterized by dysplastic hematopoiesis and increased risk of transformation into acute myeloid leukemia (AML) [1]
More clonotypes were found in healthy donors compared to MDS patients at all complementary determining region 3 (CDR3) lengths and significantly more at lengths of 14, 15 and 19 amino acids (Figure 1C) consistent with higher richness in healthy bone marrows. These findings indicate that the T-cell receptor (TCR) repertoire of MDS patients is significantly less diverse than healthy donors, these findings may be hampered by the healthy donors being younger than MDS patients
hypomethylating agents (HMAs), which constitute the mainstay treatment of MDS, have an immunomodulatory role that alter T-cell functions [27, 28]
Summary
Myelodysplastic syndrome (MDS) is a clonal hematologic disorder characterized by dysplastic hematopoiesis and increased risk of transformation into acute myeloid leukemia (AML) [1]. Hypomethylating agents (HMA), such as azacitidine and decitabine, are the mainstay of MDS treatment leading to decreased transfusion requirements and improved quality of life [1, 2]. T-cell dysregulation [6, 7], T-cell inhibition of hematopoietic precursors [8], and auto-immune T-cell activity may lead to selection of dysplastic clones in MDS [6]. 10% of MDS patients have autoimmune clinical manifestations including vasculitis, dermatitis and nephritis [9]. Evaluating T-cell dynamics in response to HMA treatment in MDS is warranted to evaluate whether clinical responses are mediated via Tcell modulation
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