Characteristic of TIGIT and DNAM-1 Expression on Foxp3+ γδ T Cells in AML Patients

Abstract

Foxp3+ γδ regulatory T (γδ Treg) cells promote tumor growth by various mechanisms and induce immuno-senescence. The novel immune checkpoint coinhibitory receptor T cell Ig and ITIM domain (TIGIT) shares similar ligands as the costimulatory receptor DNAX accessory molecule 1 (DNAM-1) and suppresses T cell responses in tumor patients. This study is aimed at characterizing whether the TIGIT/DNAM-1 axis is involved in the distribution and expression of Foxp3+ γδ Treg cell subsets in acute myeloid leukemia (AML) patients of different clinical statuses: de novo AML (27 patients), AML in nonremission (NR) (7 patients), and AML in complete remission (CR) (12 patients). Our data demonstrated that the proportions of Foxp3+, TIGIT+Foxp3+, and DNAM-1+Foxp3+ γδ T cells are significantly higher in de novo and NR patients. High levels of TIGIT and DNAM-1 on Foxp3+ γδ T cells correlated with increased Foxp3+ γδ T cell frequencies. In addition, a high TIGIT/DNAM-1 ratio was observed in de novo AML patients and healthy individuals (HIs). Furthermore, the phenotypic abnormalities in Foxp3+, TIGIT+Foxp3+, and DNAM-1+Foxp3+ γδ T cells were restored when the patients achieved CR after chemotherapy. Moreover, higher TIGIT+Foxp3+ γδ T cells were associated with AML patients who had poor overall survival and were an independent risk factor for prognosis. In conclusion, our study reveals for the first time that the TIGIT/DNAM-1 axis may be involved in Foxp3+ γδ Treg cells and indicates the clinical progression and prognosis of AML patients of different clinical statuses, which is considered beneficial for efficient AML immunotherapy.

Bone Marrow-Resident Vδ1 T Cells Co-express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma

“…Although the knowledge of checkpoint expression on γδ T cells is still sparse, our observations of an increased frequency of TIGIT + γδ T cells confirm the data of increased levels of TIGIT + γδ T cells in de novo AML patients published by Jin et al In their study, upregulation of TIGIT on γδ T cells was associated with a lower overall survival rate for non-M3 AML (38). To our knowledge, there is no publication of the TIGIT expression on γδ T cells in MM.…”

“…Regarding the (co)-expression of these checkpoints on γδ T cells, little is known. Jin et al showed for the first time that TIGIT is also expressed by regulatory Forkhead-Box-Protein P3 (FOXP3) + γδ T cells in AML ( 38 ). Moreover, it has been presented that tumor-infiltrating γδ T cells express the ectonucleotidases CD39 and CD73 and may be dysfunctional via the activation of adenosine-mediated pathways ( 39 , 40 ).…”

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

“…Other NKRs, such as DNAX accessory molecule-1 (DNAM-1), can identify their ligands, such as the polyoma virus receptor (PVR) and nectin-2 molecules, in LCs (74,158). Although a negative role has been reported for DNAM-1 expression in leukemia (159), this co-receptor is involved in the activation of gd T cell cytotoxicity after interaction with their ligands in leukemic blasts. This is evidenced when Vg9Vd2 cells kill LCs in a TCR and DNAM-1 dependent fashion, with robust secretion of perforins and granzymes (74).…”

“…In addition to PD1/PD-L1, other inhibitory proteins are highly regulated in LCs (i.e., CTLA4, BTLA, TIGIT, TIM3 and LAG3) and their effects on gd T cells have not yet been fully investigated (26,159,(214)(215)(216). However, previous studies have shown that some of these receptors have great potential for deregulating their antitumor activity, reflecting in cytokine production (213,217).…”

The Roles of γδ T Cells in Hematopoietic Stem Cell Transplantation

“…Distinct subsets of γδ T cells, especially γδ Tregs, can also play an important role in HSCT 7 . We found that γδ Tregs expressed the novel immune checkpoint receptors T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD226, and DNAX accessory molecule-1 (DNAM-1) in aute myeloid leukemia (AML) patients and the expressions were associated with clinical outcomes 22 , 23 . γδ Tregs were also found to inhibit the proliferation of CD4 + CD25 − T cells in patients with multiple myeloma 24 .…”