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Tissue-resident memory T (TRM) cells infiltrating solid tumors could influence tumor progression and the response to immune therapies. However, the proportion and prognostic value of TRM cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) are unclear. In this study, we used flow cytometry to assay the phenotype of 49 BM samples from patients newly diagnosed with AML (ND-AML). We found that the BM CD8+ effector memory (TEM) cells highly expressed CD69 (CD8+ TRM-like T cells), and their percentage was significantly increased in patients with ND-AML compared with that in healthy individuals (HI). The high percentage of CD8+ TRM-like subset was associated with poor overall survival in our ND-AML cohort. The Kaplan–Meier Plotter database verified a significantly reduced survival rate among patients with high expression of CD8+ TRM-like T cell characteristic genes (CD8A, CD69, and TOX), especially the M4 and M5 subtypes. Phenotypic analysis revealed that the BM CD8+ TRM-like subpopulation exhibited exhausted T cell characteristics, but its high expression of CD27 and CD28 and low expression of CD57 suggested its high proliferative potential. The single-cell proteogenomic dataset confirmed the existence of TRM-like CD8+ T cells in the BM of patients with AML and verified the high expression of immune checkpoints and costimulatory molecules. In conclusion, we found that the accumulation of BM CD8+ TRM-like cells could be an immune-related survival prediction marker for patients with AML.

Abstract Venetoclax, an inhibitor that selectively targets B cell lymphoma-2 (BCL-2) that has been approved for treating adult acute myeloid leukemia (AML) in combination with hypomethylating agents. However, its short duration of response and emergence of resistance are significant issues. In this study, we found that the sensitivity of AML cells to venetoclax was considerably enhanced by ML385, an inhibitor of the ferroptosis factor nuclear transcription factor erythroid 2-related factor 2 (NRF2). Using AML samples, we verified that NRF2 and its target gene ferritin heavy chain 1 (FTH1) were highly expressed in patients with AML and correlated with poor prognosis. Downregulation of NRF2 could inhibit FTH1 expression and significantly enhance the venetoclax-induced labile iron pool and lipid peroxidation. By contrast, NRF2 overexpression or administration of the reactive oxygen species inhibitor N-acetylcysteine and vitamin E could effectively suppress the anti-AML effects of ML385+venetoclax. Furthermore, the ferroptosis inducer erastin increased the anti-AML effects of venetoclax. Our study demonstrated that NRF2 inhibition could enhance the AML cell death induced by venetoclax via the ferroptosis pathway. Thus, the combination of ML385 with venetoclax may offer a favorable strategy for AML treatment.

Abstract Background Acute myeloid leukemia (AML) is an aggressive heterogeneous hematological malignancy with remarkably heterogeneous outcomes. This study aimed to identify potential biomarkers for AML risk stratification via analysis of gene expression profiles. Methods RNA sequencing data from 167 adult AML patients in the Cancer Genome Atlas (TCGA) database were obtained for overall survival (OS) analysis, and 52 bone marrow (BM) samples from our clinical center were used for validation. Additionally, siRNA was used to investigate the role of prognostic genes in the apoptosis and proliferation of AML cells. Results Co‐expression of 103 long non‐coding RNAs (lncRNAs) and mRNAs in the red module that were positively correlated with European Leukemia Network (ELN) risk stratification and age was identified by weighted gene co‐expression network analysis (WGCNA). After screening by uni‐ and multivariate Cox regression, Kaplan–Meier survival, and protein–protein interaction analysis, four genes including the lncRNA LOC541471, GDAP1, SOD1, and STK25 were incorporated into calculating a risk score from coefficients of the multivariate Cox regression model. Notably, GDAP1 expression was the greatest contributor to OS among the four genes. Interestingly, the risk score, ELN risk stratification, and age were independent prognostic factors for AML patients, and a nomogram model constructed with these factors could illustrate and personalize the 1‐, 3‐, and 5‐year OS rates of AML patients. The calibration and time‐dependent receiver operating characteristic curves (ROCs) suggested that the nomogram had a good predictive performance. Furthermore, new risk stratification was developed for AML patients based on the nomogram model. Importantly, knockdown of LOC541471, GDPA1, SOD1, or STK25 promoted apoptosis and inhibited the proliferation of THP‐1 cells compared to controls. Conclusions High expression of LOC541471, GDAP1, SOD1, and STK25 may be biomarkers for risk stratification of AML patients, which may provide novel insight into evaluating prognosis, monitoring progression, and designing combinational targeted therapies.

Objective T cell dysfunction is a common characteristic of patients with myeloid leukemia and is closely related to clinical efficacy and prognosis. In order to clarify the mechanisms leading to the T cell dysfunction, we characterized the gene expression profile of T cells from chronic myelogenous leukemia (CML) patients by microarray analysis and investigated the related regulating pathway.Methods We employed gene expression profiling, bioinformatics and real-time quantitative reverse transcription PCR (RT-qPCR) to detect genes differentially expressed in CML patients versus healthy donors.Results There were 1704 genes differentially expressed between CD3+ T cells from CML patients and healthy donors, including 868 up-regulated genes and 836 down-regulated genes, which mostly related to T cell functional pathways. In particular, lower expression of NFATC1, a member of the TCR signaling pathway, was detected in CD3+ T cells from CML patients. We further found that the expression of IRF4 and BACH2, transcription factors that potentially regulate NFATC1, in CD3+ T cells from CML patients was significantly lower than that in healthy donors.Conclusion We for the first time observed the altered gene expression profiles of CD3+ T cells from CML patients, and the results suggested that IRF4, BACH2 and NFATC1 may be involved in regulating T cell dysfunction in CML patients in the form of a transcriptional regulatory network. These findings may provide potential targets for tyrosine kinase inhibitors in combination with other targeted immunotherapies .

Abstract Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.

Abstract The molecular mechanisms underlying cancer immune escape are a core topic in cancer immunology research. Cancer cells can escape T cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1, CD274) immune checkpoint. Studying the PD-L1 regulatory pattern of tumor cells will help elucidate the molecular mechanisms of tumor immune evasion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-L1 at the transcriptional, post-transcriptional, and post-translational levels and influence the anti-tumor immune response by regulating PD-L1. In this review, we focus on the regulation of PD-L1 in cancer cells and summarize the underlying mechanisms.