Increased PD-1+Foxp3+ γδ T cells associate with poor overall survival for patients with acute myeloid leukemia

Abstract

Problemsγδ T cells are essential for anti-leukemia function in immunotherapy, however, γδ T cells have different functional subsets, including regulatory cell subsets expressing the Foxp3. Whether they are correlated with immune-checkpoint mediated T cell immune dysfunction remains unknown in patients with acute myeloid leukemia (AML).MethodsIn this study, we used RNA-seq data from 167 patients in TCGA dataset to analyze the correlation between PD-1 and FOXP3 genes and these two genes’ association with the prognosis of AML patients. The expression proportion of Foxp3+/PD-1+ cells in γδ T cells and two subgroups Vδ1 and Vδ2 T cells were performed by flow cytometry. The expression level of FOXP3 and PD-1 genes in γδ T cells were sorted from peripheral blood by MACS magnetic cell sorting technique were analyzed by quantitative real-time PCR.ResultsWe found that PD-1 gene was positively correlated with FOXP3 gene and highly co-expressed PD-1 and FOXP3 genes were associated with poor overall survival (OS) from TCGA database. Then, we detected a skewed distribution of γδ T cells with increased Vδ1 and decreased Vδ2 T cell subsets in AML. Moreover, significantly higher percentages of PD-1+ γδ, Foxp3+ γδ, and PD-1+Foxp3+ γδ T cells were detected in de novo AML patients compared with healthy individuals. More importantly, AML patients containing higher PD-1+Foxp3+ γδ T cells had lower OS, which might be a potential therapeutic target for leukemia immunotherapy.ConclusionA significant increase in the PD-1+Foxp3+ γδ T cell subset in AML was associated with poor clinical outcome, which provides predictive value for the study of AML patients.

High percentage of bone marrow CD8+ tissue-resident-like T cells predicts inferior survival in patients with acute myeloid leukemia

“…Among all hematologic malignancies, Hodgkin's lymphoma has the greatest bene t from treatment with ICIs, and the major immunosuppressive effector cells present in Hodgkin's lymphoma TME appear to be exhausted PD-1 + Th1 effector cells [11]. Although a high percentage of T cells with exhaustion phenotypes was detected in AML by our team and many other research groups [12,13,14,15,16], the use of ICIs in AML is challenging partly because leukemia cells employ various cell-autonomous and cell-nonautonomous mechanisms to reprogram the systemic and bone marrow microenvironment (BMM) to become immune privileged [17,18]. To date, the FDA has not approved such drugs for AML.…”

Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements

“… 88 , 118 Other studies contradict the above viewpoints, suggesting that high numbers of PD-1+ γδ T cells are correlated with a poor prognosis for patients with acute leukemia. 119 In HCC cell lines, the cytotoxicity of PD-1+ γδ T cells is weakened. 49 Deeper exploration of the relationship between γδ T cells and PD-1 expression will lead to a more comprehensive understanding of immunotherapy.…”

γδ T cells and the PD-1/PD-L1 axis: a love–hate relationship in the tumor microenvironment

“…The proportion of PD-1 + TIM3 + Vδ2 T cells is strongly higher in individuals with acute myeloid leukemia (AML) than in healthy controls [ 31 ]. Additionally, analysis of PB samples from AML patients in The Cancer Genome Atlas (TCGA) database revealed that elevated levels of FOXP3 and PD-1 co-expression on γδ T cells were associated with adverse clinical outcomes [ 32 ]. Similarly, γδ TILs in colon cancer mainly express PD-1 + CD8α − [ 33 ], in contrast to γδ T cells from PB and adjacent normal colon tissue, which display an effector phenotype but a diminished ability to secrete IFN-γ [ 26 ].…”

“…Notably, the Vδ1 T cell population is greater among γδ T cells within primary tumors and malignant ascites lymphocytes (MALs) in ovarian cancer (OC) [ 40 ], as well as resident in the bone marrow (BM) of AML and MM patients [ 41 ]. An increased percentage of Vδ1 T cells positive for FOXP3 [ 32 ], CD39, PD-1 and TIM3 was primarily observed, which is characterized by elevated co-expression of multiple immunosuppressive molecules with TIGIT [ 41 ]. The differentiation of Vδ1 T cells in TILs and MALs in OC differs: the majority of Vδ1 TILs exhibit a T EM phenotype, while Vδ1 MALs exhibit a more mature T EMRA phenotype.…”