Recurrence in isolated distal DVT after anticoagulation: a systematic review and meta-analysis of axial and muscular venous thrombosis.

OBJECTIVE: To identify recurrent venous thromboembolism (VTE) after discontinuation of anticoagulation in patients with isolated distal deep vein thrombosis based on its anatomic localization (axial or muscular veins). METHODS: Data were sourced from PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases in the time period up to October 2023. The study followed PRISMA guidelines using a registered protocol (CRD42023443029). Studies reporting recurrent VTE in patients with axial or muscular DVT were included in the analysis. RESULTS: Five studies with a total of 1,403 participants were evaluated. The results showed a pooled odds ratio of 1.12 (95% confidence interval 0.77-1.63) between axial and muscular DVT. Heterogeneity was low (I2 = 0%, p = 0.91) and there was no significant difference in the rate of recurrent VTE between axial and muscular DVT in each subgroup. CONCLUSIONS: Muscular and axial DVT showed comparable recurrent VTE rates after anticoagulation. However, uncertainties regarding the possibility of recurrence affecting the popliteal vein or resulting in pulmonary embolism following muscular DVT anticoagulation persisted. Randomized trials in patients with isolated distal DVT are still needed to clarify its prognosis for different anatomical thrombus locations.

Analysis of prognostic biomarker models of TXNIP/NLRP3/IL1B inflammasome pathway in patients with acute myeloid leukemia.

Background: Exploring potential biomarkers for predicting clinical outcomes and developing targeted therapies for acute myeloid leukemia (AML) is of utmost importance. This study aimed to investigate the expression pattern of the thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway and its role in the prognosis of AML patients. Methods: In this study, we examined the prognostic value of TXNIP/NLRP3 pathway in AML patients using microarray data from Gene Expression Omnibus (GEO) and transcriptome data from the Cancer Genome Atlas (TCGA) to develop a prognostic model and validated the results by quantitative real-time PCR (qRT-PCR) in a validation cohort of 26 AML patients and 18 healthy individuals from Jinan University (JNU) database. Results: Analysis of the GSE13159 database revealed that TXNIP, interleukin 1 beta (IL1B) within the TXNIP/NLRP3 pathway were significantly upregulated and caspase1 (CASP1) was downregulated in AML patients (TXNIP, P = 0.031; IL1B, P = 0.042; CASP1, P = 0.038). Compared to high NLRP3 expression, AML patients with low NLRP3 expression had a longer overall survival (OS) in the GSE12417 dataset (P = 0.004). Moreover, both the training and validation results indicated that lower TXNIP, NLRP3, and IL1B expression were associated with favorable prognosis (GSE12417, P = 0.009; TCGA, P = 0.050; JNU, P = 0.026). According to the receiver operating characteristic curve analysis, this model demonstrated a sensitivity of 84% for predicting three-year survival. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using TXNIP/NLRP3/IL1B genes in novel targeted therapies for AML.

Validation of a pulmonary embolism risk assessment model in gynecological inpatients : Clinical trial: A single-center, retrospective study.

OBJECTIVE: To compare the predictive efficacy of the PADUA and Caprini models for pulmonary embolism (PE) in gynecological inpatients, analyze the risk factors for PE, and validate whether both models can effectively predict mortality rates. METHODS: A total of 355 gynecological inpatients who underwent computed tomography pulmonary angiography (CTPA) were included in the retrospective analysis. The comparative assessment of the predictive capabilities for PE between the PADUA and Caprini was carried out using receiver operating characteristic (ROC) curves. Logistic regression analysis was used to identify risk factors associated with PE. Additionally, Kaplan-Meier survival analysis plots were generated to validate the predictive efficacy for mortality rates. RESULTS: Among 355 patients, the PADUA and Caprini demonstrated the area under the curve (AUC) values of 0.757 and 0.756, respectively. There was no statistically significant difference in the AUC between the two models (P = 0.9542). Multivariate logistic analysis revealed immobility (P < 0.001), history of venous thromboembolism (VTE) (P = 0.002), thrombophilia (P < 0.001), hormonal treatment (P = 0.022), and obesity (P = 0.019) as independent risk factors for PE. Kaplan-Meier survival analysis demonstrated the reliable predictive efficacy of both the Caprini (P = 0.00051) and PADUA (P = 0.00031) for mortality. ROC for the three- and six-month follow-ups suggested that the Caprini model exhibited superior predictive efficacy for mortality. CONCLUSIONS: The PADUA model can serve as a simple and effective tool for stratifying high-risk gynecological inpatients before undergoing CTPA. The Caprini model demonstrated superior predictive efficacy for mortality rates.

Higher TIGIT+ γδ TCM cells may predict poor prognosis in younger adult patients with non-acute promyelocytic AML.

Introduction: γδ T cells recognize and exert cytotoxicity against tumor cells. They are also considered potential immune cells for immunotherapy. Our previous study revealed that the altered expression of immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on γδ T cells may result in immunosuppression and is possibly associated with a poor overall survival in acute myeloid leukemia (AML). However, whether γδ T-cell memory subsets are predominantly involved and whether they have a relationship with clinical outcomes in patients with AML under the age of 65 remain unclear. Methods: In this study, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of γδ T-cell subsets, including central memory γδ T cells (TCM γδ), effector memory γδ T cells (TEM γδ), and TEM expressing CD45RA (TEMRA γδ), in peripheral blood from 30 young (≤65 years old) patients with newly diagnosed non-acute promyelocytic leukemia (also known as M3) AML (AMLy-DN), 14 young patients with AML in complete remission (AMLy-CR), and 30 healthy individuals (HIs). Results: Compared with HIs, patients with AMLy-DN exhibited a significantly higher differentiation of γδ T cells, which was characterized by decreased TCM γδ cells and increased TEMRA γδ cells. A generally higher TIGIT expression was observed in γδ T cells and relative subsets in patients with AMLy-DN, which was partially recovered in patients with AMLy-CR. Furthermore, 17 paired bone marrow from patients with AMLy-DN contained higher percentages of γδ and TIGIT+ γδ T cells and a lower percentage of TCM γδ T cells. Multivariate logistic regression analyses revealed the association of high percentage of TIGIT+ TCM γδ T cells with an increased risk of poor induction chemotherapy response. Conclusions: In this study, we investigated the distribution of γδ T cells and their memory subsets in patients with non-M3 AML and suggested TIGIT+ TCM γδ T cells as potential predictive markers of induction chemotherapy response.

CD69 is a Promising Immunotherapy and Prognosis Prediction Target in Cancer.

Immunotherapy utilizing T cells that attack tumors is a promising strategy for treatment, but immune suppressive T cell subsets, such as regulatory T cell (Treg), and immune checkpoint molecules, including programmed death-1 (PD-1), can suppress the intensity of a T cell immune reaction and thereby impair tumor clearance. Cluster of differentiation 69 (CD69), known as an early leukocyte activation marker, can be used as a measure or early marker of T cell activation. In recent years, the functions of CD69 in the regulation of Treg/Th17 (T helper cell 17) differentiation and in the tissue retention of T cells have attracted considerable interest. These functions are related to the role of CD69 in immune suppression in tumor environments (TME). In this review, we first summarized current perspectives in the biological function of CD69 and demonstrated that CD69 acts as a regulator of T cell activation, differentiation, retention, and exhaustion. Then, we discussed recent advances in understanding of CD69 deficiency and anti-CD69 antibody administration and shed light on the value of targeting on CD69 for cancer immunotherapy and prognosis prediction.

Nomogram for predicting pulmonary embolism in gynecologic inpatients with isolated distal deep venous thrombosis.

OBJECTIVE: To investigate the incidence of isolated distal deep venous thrombosis (IDDVT) concurrent with pulmonary embolism (PE) in gynecologic inpatients, analyze the risk factors for IDDVT with PE, and establish a nomogram model for IDDVT patients with PE. METHODS: A total of 260 patients were diagnosed with IDDVT between December 2017 and November 2020. The incidence of PE in these patients was determined using computed tomography pulmonary angiography. Logistic regression analysis was used to identify the related risk factors. On this basis, nomogram risk prediction models were established. RESULTS: Among 260 patients with IDDVT, 106 (40.8%) had concurrent PE, of whom 74 (28.5%) experienced silent PE. Univariate logistic analysis demonstrated statistical significance for body mass index (BMI; P = 0.044), glucocorticoid therapy (P = 0.009), hypertension (P < 0.001), and diabetes (P < 0.001). Multivariate logistic analysis revealed that these were independent risk factors for IDDVT with PE that retained statistical significance. A nomogram based on these factors was constructed to predict PE in patients with IDDVT. Its receiver operating characteristic (ROC) showed an area under the curve of 0.710 (95% confidence interval 0.642-0.779), with prediction sensitivity of 64.2% and prediction specificity of 76.6%. CONCLUSIONS: In the present study, a high prevalence of PE was found in gynecologic inpatients with IDDVT. Glucocorticoid therapy, hypertension, diabetes, and BMI were independent risk factors for IDDVT patients with PE. Taking these risk factors into account, a nomogram risk prediction model was developed to help facilitate early detection of concurrent PE.

A randomized controlled trial of standard vs customized graduated elastic compression stockings in patients with chronic venous disease.

OBJECTIVE: This study aimed to compare the efficacy of customized graduated elastic compression stockings (c-GECSs) based on lower leg parameter models with standard GECSs (s-GECSs) in patients with chronic venous disease (CVD). METHODS: In this randomized, single-blind, controlled trial, 79 patients with stage C2 or C3 CVD were assigned to one of two groups: c-GECSs or s-GECSs. The primary outcome was change to Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) scores at months 1, 3, and 6 as compared with baseline. Secondary outcomes included compliance with wearing ECSs, interface pressure at the smallest circumference of the ankle (point B) and the largest circumference of the calf (point C), and calf volume (CV). RESULTS: There were 13 pairs of s-GECS and 2 pairs of c-GECS that showed pressure values higher than the standard at either point B or C. The c-GECSs were significantly superior to s-GECSs in terms of score improvement at all three time points (month 1, 8.47 [95% confidence interval (CI), 7.47-9.45] vs 5.89 [95% CI, 5.00-6.78]; month 3, 9.60 [95% CI, 8.47-10.72] vs 6.72 [95% CI, 5.62-7.83]; month 6, 7.09 [95% CI, 5.93-8.24] vs 3.92 [95% CI, 2.67-5.18]; P < .0001). Besides, at month 1, the mean daily use time of the c-GECS and s-GECS groups was 10.7 and 9.5 hours, respectively (P < .05). Correlation analysis indicated a negative relationship between local high pressure and daily duration in the s-GECS group (rpb = -0.388; n = 38; P < .05). Variances in pressure were greater in the s-GECSs group. The c-GECSs showed advantage in maintaining pressure. Both c-GECSs and s-GECSs effectively reduced CV (mL), with no significant differences between groups (month 1, 90.0 [95% CI, 71.4-108.5] vs 85.0 [95% CI, 65.6-104.2]; month 3, 93.8 [95% CI, 69.7-117.8] vs 85.9 [95% CI, 65.5-106.2]; month 6, 70.8 [95% CI, 46.5-95.2]) vs 60.8 [95% CI, 44.1-77.5]). CONCLUSIONS: The c-GECSs based on individual leg parameter models significantly improved VEINES-QOL scores and provided stable and enduring pressure as compared with s-GECSs for patients with stage C2 or C3 CVD. Although both c-GECSs and s-GECSs effectively reduced CV, the superior fit and comfort of c-GECSs improved patient compliance. Hence, c-GECSs are a viable alternative for patients who have difficulty tolerating s-GECSs.

Development and validation of a graduated compression stockings adherence scale.

OBJECTIVE: Compression therapy with the use of graduated compression stockings (GCSs) is a common treatment strategy for chronic venous disease (CVD). However, there is no uniform and objective standard to assess adherence to the use of GCSs. The aim of this study is to develop and validate a GCS Compliance Scale (GCSAS) to fill gaps in internationally recognized comprehensive scales and provide a useful tool for future research. METHODS: The items included in the GCSAS were based on a review of the literature and open-ended interviews with experts, who screened the initial items using an item-level content validity index. Then, pilot tests were conducted three times with 50 participants. After exclusion of redundant and cross-loading items by exploratory factor analysis, 290 subjects were recruited to evaluate the reliability and validity of the proposed GCSAS. Analyses included internal consistency, test-retest reliability, split-half reliability, construct validity, criterion validity, convergent validity, and discriminant validity. RESULTS: The final GCSAS consisted of 17 items and 5 dimensions. The results of the exploratory factor analysis indicated that the variances of each factor explained were 22.03%, 14.85%, 14.74%, 14.16%, and 13.35%, and all 5 factors explained 79.13% of the variance among the 17 items. The factor loadings of all items were >0.7. Confirmatory factor analysis indicated that the indices were adequate. A significant positive correlation was found between the GCSAS and the Venous Insufficiency Epidemiological and Economic Study - Quality of Life questionnaire scores (r = 0.76, p < 0.001). The Cronbach's alpha coefficient was 0.90, test-retest reliability was 0.81, and split-half reliability was 0.92. CONCLUSIONS: The GCSAS showed good validity and reliability to assess compliance with the use of GCSs among patients with CVD.

Identification of immune infiltration-related biomarkers in carotid atherosclerotic plaques.

Atherosclerosis is a chronic lipid-driven inflammatory response of the innate and adaptive immune systems, and it is responsible for several cardiovascular ischemic events. The present study aimed to determine immune infiltration-related biomarkers in carotid atherosclerotic plaques (CAPs). Gene expression profiles of CAPs were extracted from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between the CAPs and control groups were screened by the "limma" package in R software. Immune cell infiltration between the CAPs and control groups was evaluated by the single sample gene set enrichment analysis. Key infiltrating immune cells in the CAPs group were screened by the Wilcoxon test and least absolute shrinkage and selection operator regression. The weighted gene co-expression network analysis was used to identify immune cell-related genes. Hub genes were identified by the protein-protein interaction (PPI) network. Receiver operating characteristic curve analysis was performed to assess the gene's ability to differentiate between the CAPs and control groups. Finally, we constructed a miRNA-gene-transcription factor network of hub genes by using the ENCODE database. Eleven different types of immune infiltration-related cells were identified between the CAPs and control groups. A total of 1,586 differentially expressed immunity-related genes were obtained through intersection between DEGs and immune-related genes. Twenty hub genes were screened through the PPI network. Eventually, 7 genes (BTK, LYN, PTPN11, CD163, CD4, ITGAL, and ITGB7) were identified as the hub genes of CAPs, and these genes may serve as the estimable drug targets for patients with CAPs.

The ectonucleotidases CD39 and CD73 on T cells: The new pillar of hematological malignancy.

Hematological malignancy develops and applies various mechanisms to induce immune escape, in part through an immunosuppressive microenvironment. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment (TME). Adenosine signaling through the A2A receptor expressed on immune cells, such as T cells, potently dampens immune responses. Extracellular adenosine generated by ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5'-nucleotidase (CD73) molecules is a newly recognized 'immune checkpoint mediator' and leads to the identification of immunosuppressive adenosine as an essential regulator in hematological malignancies. In this Review, we provide an overview of the detailed distribution and function of CD39 and CD73 ectoenzymes in the TME and the effects of CD39 and CD73 inhibition on preclinical hematological malignancy data, which provides insights into the potential clinical applications for immunotherapy.

TIGIT axis: novel immune checkpoints in anti-leukemia immunity.

Hematologic malignancy evades immune-mediated recognition through upregulating various checkpoint inhibitory receptors (IRs) on several types of lymphocytes. Immunotherapies targeting IRs have provided ample evidence supporting regulating innate and adaptive immunity and obtaining clinical benefits. Newly described IRs have received considerable attention and are under investigation in cancer immunotherapy. Specifically, T cell immunoglobulin and ITIM domain is a novel inhibitory checkpoint receptor, and its immune checkpoint axis includes additional receptors such as CD96 and CD226, which are very promising targets. However, how the dynamics and functions of these receptor networks remain unknown, this review addresses the recent findings of the relevance of this complex receptor-ligand system and discusses their potential approaches in translating these preclinical findings into novel clinical agents in anti-leukemia immunotherapy.

Utilizing exosomes as sparking clinical biomarkers and therapeutic response in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant clonal tumor originating from immature myeloid hematopoietic cells in the bone marrow with rapid progression and poor prognosis. Therefore, an in-depth exploration of the pathogenesis of AML can provide new ideas for the treatment of AML. In recent years, it has been found that exosomes play an important role in the pathogenesis of AML. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention, which are key mediators of intercellular communication. Extracellular vesicles not only affect AML cells and normal hematopoietic cells but also have an impact on the bone marrow microenvironment and immune escape, thereby promoting the progression of AML and leading to refractory relapse. It is worth noting that exosomes and the various molecules they contain are expected to become the new markers for disease monitoring and prognosis of AML, and may also function as drug carriers and vaccines to enhance the treatment of leukemia. In this review, we mainly summarize to reveal the role of exosomes in AML pathogenesis, which helps us elucidate the application of exosomes in AML diagnosis and treatment.

High TRGV 9 Subfamily Expression Marks an Improved Overall Survival in Patients With Acute Myeloid Leukemia.

Background: Heterogeneous T cells in acute myeloid leukemia (AML) have the combinatorial variety generated by different T cell receptors (TCRs). γδ T cells are a distinct subgroup of T cells containing TCRγ (TRGV) and TCRδ (TRDV) subfamilies with diverse structural and functional heterogeneity. Our previous study showed that clonally expanded TRDV T cells might benefit the immune response directed against AML. However, the features of the TRGV repertoire in AML remain unknown. To fully characterize the features of γδ T cells, we analyzed the distribution and clonality of TRGV I-III subfamilies (TRGV II is also termed TRVG 9), the proportions of γδ T cell subsets, and their effects on the overall survival (OS) of patients with AML. Methods: In this study, the complementarity-determining region 3 (CDR3) size of TRGV subfamilies in γδ T cells of peripheral blood (PB) from de novo AML patients were analyzed by Genescan analysis. Expression levels of TRGV subfamilies were performed by real-time quantitative PCR. The proportions of total γδ T cells and their Vγ9+ Vδ2+ T cells subsets were detected by multicolor flow cytometry assay. We further compared the correlation among the TRGV gene expression levels, the proportion of Vγ9+ Vδ2+ T cells, and OS in AML. Results: We first found that the distribution pattern and clonality of TRGV subfamilies were changed. The expression frequencies and gene expression levels of three TRGV subfamilies in AML samples were significantly lower than those in healthy individuals (HIs). Compared with HIs, the proportions of total γδ T cells and Vγ9+ Vδ2+ T cells were also significantly decreased in patients with AML. In addition, patients with AML who had higher expression levels of the TRGV gene and higher proportion of Vγ9+ Vδ2+ T cells showed better OS than their counterparts. Furthermore, high expression levels of TRGV 9 and proportion of Vγ9+ Vδ2+ T cells were identified as independent protective factors for complete remission in patients with AML. Conclusions: The restriction of TRGV usage might be related to the preference of usage of γδ T cells. Higher expression of TRGV subfamilies might be associated with better OS in AML. Higher TRGV 9 expression and increased Vγ9+ Vδ2+ T cells subfamilies might indicate a better prognosis in patients with AML.

Higher TIGIT+CD226- γδ T cells in Patients with Acute Myeloid Leukemia.

The diverse structural and functional heterogeneity of γδ T cells is related to their distinct role in cancer immunity. The different phenotypes of γδ T cells in patients with acute myeloid leukemia (AML) is far from clear. In particular, the expression pattern of co-inhibitory and co-stimulatory receptors on γδ T cells remains unknown. In this study, we analyzed the distribution of γδ T cell subsets by expression of the immune checkpoint co-inhibitor TIGIT (T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) and its competing co-stimulatory receptor CD226 in AML patients of different clinical statuses (including de novo AML, AML in non-remission (NR), and AML in complete remission (CR)). Our data demonstrated an imbalanced distribution of TIGIT and CD226 on γδ T cells with a decrease in CD226+ γδ T cells and an increase in TIGIT+ γδ T cells in de novo AML patients, while TIGIT-CD226+ γδ T cells were restored in AML patients who achieved CR after chemotherapy. Moreover, the patients who had higher TIGIT+CD226- γδ T cells showed lower overall survival rate for non-M3 AML, which may be considered a novel prognostic immune biomarker. In conclusion, our study reveals for the first time that imbalance in the TIGIT/CD226 axis might be related to different clinical outcomes for AML patients.Abbreviations: AML: acute myeloid leukemia; CR: complete remission; ICs: immune checkpoints; PD-1: programmed death-1; γδ T cells: gamma delta T cells; TCR: T cell receptor; MHC: major histocompatibility complex; TIGIT: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; NK: natural killer; PB: Peripheral blood; NR: non-remission; FAB: French-American-British; WHO: World Health Organization; HIs: healthy individuals; OS: overall survival.

Terminal differentiation of bone marrow NK cells and increased circulation of TIGIT+ NK cells may be related to poor outcome in acute myeloid leukemia.

AIM: In order to further understand the feature of natural killer cell (NK) dysfunction in acute myeloid leukemia (AML), The distribution of NK cell subset the expression of the inhibitory receptors immunoglobulin and ITIM domain (TIGIT), killer cell lectin-like receptor (KLRG1), and the expression of maturation marker CD57 in NK cell subsets and their correlation with patient outcomes were analyzed in this study. METHODS: We collected peripheral blood (PB) and bone marrow (BM) samples from de novo AML (AML-DN) patients, patients who achieved complete remission after chemotherapy (AML-CR), and healthy individuals. An eight-color flow cytometry panel was used to identify different NK subsets and their expression of TIGIT, CD57 and KLRG1. RESULTS: Decreased percentage of CD56dim CD16+ NK cells was found only in the PB of AML-DN and AML-CR patients but not in the BM. The expression frequency of TIGIT and KLRG1 was elevated on NK cells from the PB of AML-DN patients, while it was recovered in AML-CR patients. Moreover, a higher percentage of CD57+ CD56dim CD16+ NK cells, representing a terminally differentiated NK subset with strong cytotoxic capacity but defective replication potential, was detected in the BM of AML-DN patients and predicted sub-optimal survival for patients. CONCLUSION: The results indicated that the NK cell subsets in the PB of AML patients had an exhaustion phenotype, while the BM NK cells had a terminally differentiated phenotype, which correlated with short survival for AML patients.

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

Problems: γδ 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). Methods: In 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. Results: We 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. Conclusion: A 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.

Higher Expression of WT1 With Lower CD58 Expression may be Biomarkers for Risk Stratification of Patients With Cytogenetically Normal Acute Myeloid Leukemia.

Background: Cytogenetics at diagnosis is the most important prognostic factor for adult acute myeloid leukemia (AML), but nearly 50% of AML patients who exhibit cytogenetically normal AML (CN-AML) do not undergo effective risk stratification. Therefore, the development of potential biomarkers to further define risk stratification for CN-AML patients is worth exploring. Methods: Transcriptome data from 163 cases in the GSE12417-GPL96 dataset and 104 CN-AML patient cases in the GSE71014-GPL10558 dataset were downloaded from the Gene Expression Omnibus database for overall survival (OS) analysis and validation. Results: The combination of Wilms tumor 1 (WT1) and cluster of diffraction 58 (CD58) can predict the prognosis of CN-AML patients. High expression of WT1 and low expression of CD58 were associated with poor OS in CN-AML. Notably, when WT1 and CD58 were used to concurrently predict OS, CN-AML patients were divided into three groups: low risk, WT1lowCD58high; intermediate risk, WT1highCD58high or WT1lowCD58low; and high risk, WT1highCD58low. Compared with low-risk patients, intermediate- and high-risk patients had shorter survival time and worse OS. Furthermore, a nomogram model constructed with WT1 and CD58 may personalize and reveal the 1-, 2-, 3-, 4-, and 5-year OS rate of CN-AML patients. Both time-dependent receiver operating characteristics and calibration curves suggested that the nomogram model demonstrated good performance. Conclusion: Higher expression of WT1 with lower CD58 expression may be a potential biomarker for risk stratification of CN-AML patients. Moreover, a nomogram model constructed with WT1 and CD58 may personalize and reveal the 1-, 2-, 3-, 4-, and 5-year OS rates of CN-AML patients.

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow.

Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

Age-Related Immune Profile of the T Cell Receptor Repertoire, Thymic Recent Output Function, and miRNAs.

BACKGROUND: T cell immunity plays a central role in the body's defense system, including maintaining homeostasis and preventing tumorigenesis and viral infection. Immune system functions degenerate with age, leading to immune senescence. Physiologically, immune senescence is characterized by a decrease in T cell receptor diversity, naive T cell deficiency, and alterations in T cell immune-related miRNAs. However, little is known about the characteristics of T cell immunosenescence in Chinese individuals. RESULTS: A significant decrease in the miR-17, miR-92a, and miR-181a levels in PBMCs was detected with age. The miR-92a and miR-181a levels were upregulated in CBMCs when comparing healthy individuals to group I (0~9 years), whereas miR-17 was downregulated. The sjTREC level in PBMCs was negatively correlated with age, and a sharp decrease in sjTRECs was found between groups I and II (10~19 years). Twenty-four TCR Vß subfamilies could be detected in most samples, and most displayed polyclonality, while skewed expression of the Vß subfamilies as well as an increased oligoclonal tendency was found with age. Similarly, the frequencies of the TCR Vγ and Vδ subfamilies decreased with age, and the alteration in clonality appeared to be stable at different ages. CONCLUSION: We made the novel observation of T cell immunosenescence with age in Chinese individuals, which may provide information for immune targets to enhance the T cell immune response in immunotherapy settings for elderly patients.

Increased Expression of TIGIT/CD57 in Peripheral Blood/Bone Marrow NK Cells in Patients with Chronic Myeloid Leukemia.

The antitumor activity of NK cells in patients with chronic myeloid leukemia (CML) is inhibited by the leukemia microenvironment. Recent studies have identified that the expression of TIGIT, CD57, and KLRG1 is related to the function, maturation, and antitumor capabilities of NK cells. However, the characteristics of the expression of these genes in the peripheral blood (PB) and bone marrow (BM) from patients with CML remain unknown. In this study, we used multicolor flow cytometry to assay the quantity and phenotypic changes of NK cells in PB and BM from de novo CML (DN-CML) and CML patients acquiring molecular response (MR-CML). We found that the expression of TIGIT, which inhibits NK cell function, is increased on CD56+ and CD56dim NK cells in DN-CML PB compared with those in healthy individuals (HIs), and it is restored to normal in patients who achieve MR. We also found that the expression of CD57 on NK cells was approximately the same level in PB and BM from DN-CML patients, while decreased CD57 expression was found on CD56+ and CD56dim NK cells in HI BM compared with PB. Additionally, those two subsets were significantly increased in DN-CML BM compared to HI BM. The expression of CD57 correlates with replicative senescence and maturity for human NK cells; therefore, the increase in TIGIT on PB NK cells together with an increase in CD57 on BM NK cells may explain the subdued NK cell antileukemia capacity and proliferative ability in DN-CML patients. These results indicate that reversing the immune suppression of PB NK cells by blocking TIGIT while improving the proliferation of BM NK cells via targeting CD57 may be more effective in removing tumor cells.