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.
Highlights
Acute myeloid leukemia (AML) is the most common type of myeloid malignancy in adults, and with the exception of the acute promyelocytic leukemia (APL, M3) subtype, this disease has an overall poor prognosis with limited change in the standard of care [1, 2]
We found that the proportion of Foxp3+ γδ T cells was higher in both de novo
The results demonstrated that Foxp3+ γδ, T cell Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), and DNAX accessory molecule 1 (DNAM-1) on Foxp3+ γδ cell subsets were decreased in AML patients who achieved complete remission (CR)
Summary
Acute myeloid leukemia (AML) is the most common type of myeloid malignancy in adults, and with the exception of the acute promyelocytic leukemia (APL, M3) subtype, this disease has an overall poor prognosis with limited change in the standard of care [1, 2]. Tregs, which express the transcription factor Foxp, are characterized by their high immunosuppressive function for maintaining self-tolerance and regulating the innate and adaptive immune systems [4]. Elevated expression of Tregs in the tumor microenvironment has been reported for hematological malignancies, and this has been correlated with progression and poor survival. Cosignalling receptors, including costimulatory and coinhibitory receptors, play an indispensable role in regulating the immune response [5]. Coinhibitory receptors, such as programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte associated-4
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