Higher CD4 Research Articles

Peripheral blood lymphocyte subpopulations as predictive biomarkers for first-line programmed death 1 inhibitors efficacy in esophageal squamous cell carcinoma: A retrospective study.

Esophageal cancer (EC) poses a significant global health burden, necessitating effective treatment strategies. Immune checkpoint inhibitors have emerged as a promising therapeutic option for EC, but the identification of predictive biomarkers remains crucial for optimizing patient outcomes. We conducted a retrospective analysis of medical records from advanced esophageal squamous cell carcinoma patients treated with first-line programmed death 1 inhibitors. Peripheral blood lymphocyte subpopulations were evaluated using flow cytometry, while hematological tests provided data on neutrophil, lymphocyte, and monocyte counts. Cox regression and logistic regression analyses were employed to explore the association between lymphocyte subpopulations, baseline characteristics, and progression-free survival (PFS). Among the 100 initially included patients, 70 met eligibility criteria. Multivariate Cox regression analysis revealed a significant association between high CD16+CD56+ lymphocyte proportions and longer PFS, independent of other clinical variables. Similarly, a high CD4+/CD8+ ratio was correlated with prolonged PFS. Kaplan-Meier survival curves supported these findings. Logistic regression analysis indicated no significant differences in the CD4+/CD8+ ratio and CD16+CD56+ lymphocytes concerning baseline characteristics, suggesting their potential as independent prognostic markers. Our study highlights the predictive value of peripheral blood CD16+CD56+ lymphocytes and the CD4+/CD8+ ratio for the efficacy of programmed death 1 inhibitors in advanced esophageal squamous cell carcinoma patients. These findings underscore the importance of peripheral blood biomarkers in guiding personalized immunotherapy strategies and improving outcomes for EC patients.

Integrative analysis of H&E and IHC identifies prognostic immune subtypes in HPV related oropharyngeal cancer

BackgroundDeep learning techniques excel at identifying tumor-infiltrating lymphocytes (TILs) and immune phenotypes in hematoxylin and eosin (H&E)-stained slides. However, their ability to elucidate detailed functional characteristics of diverse cellular phenotypes within tumor immune microenvironment (TME) is limited. We aimed to enhance our understanding of cellular composition and functional characteristics across TME regions and improve patient stratification by integrating H&E with adjacent immunohistochemistry (IHC) images.MethodsA retrospective study was conducted on patients with Human Papillomavirus-positive oropharyngeal squamous cell carcinoma (OPSCC). Using paired H&E and IHC slides for 11 proteins, a deep learning pipeline was used to quantify tumor, stroma, and TILs in the TME. Patients were classified into immune inflamed (IN), immune excluded (IE), or immune desert (ID) phenotypes. By registering the IHC and H&E slides, we integrated IHC data to capture protein expression in the corresponding tumor regions. We further stratified patients into specific immune subtypes, such as IN, with increased or reduced CD8+ cells, based on the abundance of these proteins. This characterization provided functional insight into the H&E-based subtypes.ResultsAnalysis of 88 primary tumors and 70 involved lymph node tissue images reveals an improved prognosis in patients classified as IN in primary tumors with high CD8 and low CD163 expression (p = 0.007). Multivariate Cox regression analysis confirms a significantly better prognosis for these subtypes.ConclusionsIntegrating H&E and IHC data enhances the functional characterization of immune phenotypes of the TME with biological interpretability, and improves patient stratification in HPV( + ) OPSCC.

High expression of CD3+T-lymphocytes in cerebrospinal fluid increases the risk of critical cerebral hemorrhage with systemic inflammatory response syndrome (SIRS) after surgery

ObjectiveTo assess the frequency of lymphocyte subsets and other laboratory indicators in paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples from critically ill patients with intracerebral hemorrhage (ICH) who developed systemic inflammatory response syndrome (SIRS) following surgery. IntroductionNeuroinflammation and systemic inflammatory responses significantly contribute to secondary brain injury following ICH. Post-surgery SIRS is known to worsen clinical outcomes in ICH patients; however, the immune response in the CSF and PB has not been fully characterized. Understanding immunological changes in ICH patients with SIRS could lead to improved clinical management and prognostic outcomes. MethodsThis study involved a retrospective analysis of data from patients with ICH who underwent surgery in the Neurological Intensive Care Unit (NICU) of Baoding No. 1 Hospital, Hebei Province, China, between January and July 2022. Patients were divided into SIRS and non-SIRS groups based on the clinical criteria. Demographic, clinical, and laboratory data, including lymphocyte subsets in CSF and PB, were collected and analyzed. This study compared lymphocyte subsets and other inflammatory markers between the SIRS and non-SIRS groups. ResultsPatients with SIRS demonstrated higher systolic blood pressure (SBP) at admission, worse 90-day prognoses, elevated inflammatory markers, increased levels of complement proteins C3 and C4, and lower levels of immunoglobulin G (IgG) compared to patients without SIRS. Between 3–6 days post-surgery, SIRS patients showed higher percentages of CD3+T cells, CD4+T cells, and CD4+/CD8+ ratios in the CSF than non-SIRS patients. CD3+T cell percentages in the CSF were consistently higher than those in the PB and were independent of PB levels. In contrast, CD3-CD16+CD56+ natural killer (NK) cell percentages were lower in patients with SIRS. No significant differences in PB lymphocyte subsets were found between the two groups. A high CSF CD3+T cell percentage (≥85.68 %) was identified as the strongest predictor of critical ICH with SIRS after surgery, with an appropriate use criterion (AUC) of 0.7742, sensitivity of 77.42 %, specificity of 76.19 %, and 95 % CI of 0.6655–0.8829 (P < 0.0001). ConclusionElevated levels of CD3+T lymphocytes in CSF are strongly associated with an increased risk of severe cerebral hemorrhage and SIRS following surgery. These findings suggest that monitoring CSF immune markers, particularly CD3+T lymphocytes, could serve as valuable predictors for the development of SIRS in critically ill ICH patients and inform post-surgical treatment strategies.

CD8 + T-cells restrict the development of peritoneal metastasis and support the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC)

Multimodal therapy for peritoneal metastasis (PM) including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides long-term survival in highly selected colorectal cancer patients. Mechanisms behind HIPEC are unknown and may include induction of adaptive immunity. We therefore analyzed human PM samples and explored the impact of HIPEC in experimental models. Human samples from colorectal primary tumors (n = 19) and PM lesions (n = 37) were examined for the presence of CD8 + T-cells and their association with disease free (DFS) and overall survival (OS). CD8 + T cell response after HIPEC was assessed using an in-vivo PM mouse model, tumor cell lines and patient-derived tumor organoids. Patients with high intraepithelial CD8 + T cell counts showed longer DFS and OS. In the mouse model, HIPEC controlled growth of PM and increased numbers of functional granzyme positive CD8 + T cells within tumors. Cell lines and human organoids that were treated with heated chemotherapies showed immunogenic changes, reflected by significantly higher levels of MHC-class I molecules and expression of Cancer Testis Antigens Cyclin A1 and SSX-4. Using in-vitro co-culture assays, we noticed that cancer cells treated with heated chemotherapy primed dendritic cells, which subsequently enhanced effector functions of CD8 + T cells. The presence of CD8 + T-cells within PM lesions is associated with prolonged survival of patients with PM. Data from PM mouse model and in-vitro assay show that heated chemotherapies induce immunogenic changes on cancer cells leading to induction of CD8 + T-cells mediated immunity, which seems to control growth of PM lesions in mice after HIPEC.

Chemokine receptor CXCR4 based positron emission tomography imaging in systemic sclerosis-related interstitial lung disease.

To assess chemokine receptor CXCR4 expression in lung parenchyma and on peripheral immune cells in systemic sclerosis-related interstitial lung disease (SSc-ILD) patients. SSc-ILD patients underwent 68Ga- CPCR4 Trifluoroacetate positron emission tomography (PET) scan, SUVmean in different lung regions and architecturally abnormal areas, and receiver operating characteristic (ROC) curves were analyzed. CXCR4 expression on peripheral immune cells using flow cytometer was studied and correlated with the different lung regions. In addition, subset analysis of CXCR4 expression by clinical subset (early, progressive, stable), ILD pattern and anti-Scl-70 positivity were done. On PET, SSc-ILD patients showed higher median SUVmean uptake of CXCR4 in the whole lung (0.56; p< 0.0001), different lung regions and architecturally abnormal areas than controls. Highest area under curve (AUC) were observed in dorsobasal regions (AUC-0.91; p< 0.0001) and reticular with architecturally distorted areas (AUC-0.95; p< 0.0001). Progressive subset had higher whole lung median SUVmean (0.73) than early (0.49; p< 0.0001) and stable (0.45; p< 0.0001) subsets, and AUC than early and stable subsets. Usual interstitial pneumonia pattern ILD showed higher CXCR4 uptake compared with non-specific interstitial pneumonia (p= 0.0032). Additionally, a trend for higher uptake was noted in anti-Scl70 positive patients as compared with anti-Scl70 negative ones. SSc-ILD patients had higher CD4+CXCR4+T cells (p= 0.0003), and CD8+CXCR4+T cells (p= 0.0013), and showed moderate to strong association on correlation with the lung parenchymal regions. In SSc-ILD, CXCR4 expression is upregulated in both lung parenchyma and peripheral T cells, significantly in progressive and UIP subsets. CXCR4 expression is a potential tool for activity assessment and prognostication.

Tumor-infiltrating immune cell profiles and changes associate with additional trastuzumab in preoperative chemotherapy for patients with HER2-positive gastric cancer

BackgroundHER2(+) gastric cancer (GC) can benefit from trastuzumab. However, the impact of additional trastuzumab in preoperative treatment on immune cells remains largely unknown.MethodsIn cohort I, immune cells were detected by immunohistochemistry in 1321 patients. Then 88 HER2(+) patients received preoperative therapy were collected as cohort II. Immune cell profiles and changes were analyzed in paired pre- and post-operative specimens using multiple immunohistochemistry staining.ResultsIn the treatment-naive GC patients (n = 1002), CD3+ and CD8+ T cell infiltration was significantly lower in the HER2(+) GC patients together with higher FoxP3+ T cells compared with HER2(−). However, FoxP3+ T and CD20+ B cell infiltration was significantly higher in HER2(+) GC after neoadjuvant chemotherapy (n = 319). The trastuzumab-exposed group had higher CD8+ T and lower FoxP3+ T cell infiltration and CD8+ T cell was even more significant in responders. Additionally, tertiary lymphoid structure (TLS) density increased in invasion margin of residual tumors. Patients with lower TLS in the tumor core or lower FoxP3+ T cells had better overall survival in the trastuzumab-exposed group.ConclusionAddition of trastuzumab modulates the immune microenvironment, suggesting the potential mechanism of the favorable outcome of anti-HER2 therapy and providing a theoretical rationale for the combinational immunotherapy in resectable HER2(+) GC patients.

Optimized patient-specific immune checkpoint inhibitor therapies for cancer treatment based on tumor immune microenvironment modeling.

Enhancing patient response to immune checkpoint inhibitors (ICIs) is crucial in cancer immunotherapy. We aim to create a data-driven mathematical model of the tumor immune microenvironment (TIME) and utilize deep reinforcement learning (DRL) to optimize patient-specific ICI therapy combined with chemotherapy (ICC). Using patients' genomic and transcriptomic data, we develop an ordinary differential equations (ODEs)-based TIME dynamic evolutionary model to characterize interactions among chemotherapy, ICIs, immune cells, and tumor cells. A DRL agent is trained to determine the personalized optimal ICC therapy. Numerical experiments with real-world data demonstrate that the proposed TIME model can predict ICI therapy response. The DRL-derived personalized ICC therapy outperforms predefined fixed schedules. For tumors with extremely low CD8 + T cell infiltration ('extremely cold tumors'), the DRL agent recommends high-dosage chemotherapy alone. For tumors with higher CD8 + T cell infiltration ('cold' and 'hot tumors'), an appropriate chemotherapy dosage induces CD8 + T cell proliferation, enhancing ICI therapy outcomes. Specifically, for 'hot tumors', chemotherapy and ICI are administered simultaneously, while for 'cold tumors', a mid-dosage of chemotherapy makes the TIME 'hotter' before ICI administration. However, in several 'cold tumors' with rapid resistant tumor cell growth, ICC eventually fails. This study highlights the potential of utilizing real-world clinical data and DRL algorithm to develop personalized optimal ICC by understanding the complex biological dynamics of a patient's TIME. Our ODE-based TIME dynamic evolutionary model offers a theoretical framework for determining the best use of ICI, and the proposed DRL agent may guide personalized ICC schedules.

Genetically predicted N-Acetyl-L-Alanine mediates the association between CD3 on activated and secreting Tregs and Guillain-Barre syndrome.

This study sought to explore the potential causal relationships among immune cell traits, Guillain-Barre syndrome (GBS) and metabolites. Employing a two-sample Mendelian randomization (MR) approach, the study investigated the causal associations between 731 immune cell traits, 1400 metabolite levels and GBS leveraging summary-level data from a genome-wide association study (GWAS). To ensure the reliability of our findings, we further assessed horizontal pleiotropy and heterogeneity and evaluated the stability of MR results using the Leave-one-out method. This study revealed a causal relationship between CD3 on activated & secreting Tregs and GBS. Higher CD3 on activated and secreting Regulatory Tregs increased the risk of GBS (primary MR analysis odds ratio (OR) 1.31/SD increase, 95% confidence interval (CI) 1.08-1.58, p = 0.005). There was no reverse causality for GBS on CD3 on activated & secreting Tregs (p = 0.36). Plasma metabolite N-Acetyl-L-Alanine (ALA) was significantly positively correlated with GBS by using the IVW method (OR = 2.04, 95% CI, 1.26-3.30; p = 0.00038). CD3 on activated & secreting Tregs was found to be positively associated with ALA risk (IVW method, OR, 1.04; [95% CI, 1.01-1.07], p = 0.0078). Mediation MR analysis indicated the mediated proportion of CD3 on activated & secreting Tregs mediated by ALA was 10% (95%CI 2.63%, 17.4%). In conclusion, our study identified a causal relationship between the level of CD3 on activated & secreting Tregs and GBS by genetic means, with a considerable proportion of the effect mediated by ALA. In clinical practice, thus providing guidance for future clinical research.

Efficacy and safety of camrelizumab combined with chemotherapy in the treatment of advanced biliary malignancy and associations between peripheral blood lymphocyte subsets and clinical outcomes.

Biliary tract cancer (BTC) is a highly heterogeneous aggressive tumor, and advanced patients have poor prognosis. This work aimed to evaluate the efficacy and safety of camrelizumab combined with chemotherapy in treating advanced BTC, and to explore predictive biomarkers for distinguishing effective population. 183 advanced BTC patients admitted from September 2018 to September 2021 were retrospectively selected. 93 patients were treated with camrelizumab combined with chemotherapy (C+C group) and 90 patients were treated with chemotherapy alone (C group). Objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were analyzed between two groups. Peripheral blood lymphocyte subsets were assessed by flow cytometry pre- and post-treatment. The mPFS (6.9 months) and mOS (12.1 months) in the C+C group were significantly longer than those in the C group, which were 5.2 months and 9.8 months respectively (HR 0.46, 95% CI 0.38-0.54, p=0.017; HR 0.39, 95% CI 0.32-0.47, p=0.033). The percentage of Total T, CD4+T, natural killer (NK) cells, lymphocyte, and CD4+/CD8+ cell ratios were significantly increased in effective patients after C+C treatment, but didn't increase in progressive disease (PD) patients. Higher percentage of Total T, CD4+T, and higher CD4+/CD8+ cell ratios post-treatment were associated with longer OS. Camrelizumab combining chemotherapy significantly prolonged the mPFS and mOS of advanced BTC patients. Immunotherapy may improve the immune status of advanced patients, and immunotherapy efficacy might be predicted based on the peripheral blood lymphocyte subsets.

Small extracellular vesicles as biomarkers of response in recurrent/metastatic HNSCC patients treated with immunotherapy

BackgroundBiomarkers that effectively predict response to anti-PD-1 mAb therapy in cancer patients are an unmet need. We evaluated the utility of small extracellular vesicles (sEV) as biomarkers of response to immunotherapy in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients.MethodsPlasma sEV were isolated from 24 R/M HNSCC patients prior to immunotherapy initiation. sEV were separated by immune capture into T cell-derived CD3(+) and tumor-enriched CD3(−) subsets. Stimulatory and suppressive profiles of CD3(−) sEV were determined by on-bead flow cytometry. Differences were assessed using nonparametric tests. Multivariable Cox regression was used to evaluate the relationship with overall (OS) and progression free survival (PFS).ResultsCD3(−)CD44v3(+) sEV represented the majority of plasma sEV; the T-cell-derived CD3(+) fraction was significantly smaller. High CD3(+) sEV was associated with better OS and PFS. Total CD3(−)CD44v3(+) sEV was not associated with outcome. However, suppressive and stimulatory profiles were associated with OS; the suppressive/stimulatory ratio was associated with best response. Exploration of individual proteins on CD3(−) sEV showed that high PD-L1 and high CTLA-4 were associated with better outcomes.ConclusionsEvaluation of the T cell-derived-CD3(+) and tumor-enriched CD3(−) plasma sEV subsets indicated their potential utility as biomarkers of response to immunotherapy.

CD25+FOXP3+CD45RA− regulatory T-cell infiltration as a prognostic biomarker for endometrial carcinoma

BackgroundRegulatory T (Treg) cells reportedly play crucial roles in tumor angiogenesis as well as antitumor immunity. In order to explore their therapeutic potential, we investigated the precise prognostic impact of Treg markers in endometrial carcinoma.MethodsWe performed multiplexed immunofluorescence and quantitative image analyses of CD25, FOXP3, CTLA4, and CD45RA in tumor specimens from 176 consecutive patients treated at our institution for primary endometrial carcinomas. Bioinformatics analyses were further conducted to corroborate the findings.ResultsHigh CD25+, FOXP3+, and CD25+FOXP3+CD45RA− stromal cell counts correlated with better overall survival (OS) (p = 0.00019, 0.028 and 0.0012) and MSI-high (p = 0.015, 0.016 and 0.047). High CD45RA+ stromal cell count was associated with superficial myometrial invasion (p = 0.0038). Bioinformatics survival analysis by Kaplan-Meier plotter showed that high CD25, FOXP3, CTLA4, and CD45RA mRNA expressions correlated with better OS (p = 0.046, 0.00042, 0.000044, and 0.0022). Univariate and multivariate analyses with various clinicopathologic prognostic factors indicated that high CD25+ or CD25+FOXP3+CD45RA− stromal cell count was significant and independent for favorable OS (p = 0.0053 and 0.0015). We subsequently analyzed the correlations between the multiplexed immunofluorescence results and treatment-free interval (TFI) after primary chemotherapy in recurrent cases, finding no significant associations. Further analysis revealed that high ratio of CD25+ : CD8+ cell count or CD25+FOXP3+CD45RA− : CD8+ cell count correlated with longer TFI (p = 0.021 and 0.021).ConclusionThe current observations suggest that the balance between CD25+ or CD25+FOXP3+CD45RA− cells and CD8+ cells, corresponding to promoting or inhibiting effect on tumor angiogenesis, affect tumor chemosensitivity leading to prognostic significance. CD25+FOXP3+CD45RA− effector Treg tumor infiltration may serve as a useful prognostic biomarker and a potential target for immunotherapeutic manipulation of tumor chemosensitivity by novel management for advanced/recurrent endometrial carcinomas.

Trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio in patients with HIV and long-term virological suppression based on Yunnan HIV cohort.

Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/μL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/μL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

Evaluation of CD4+ CD25+/high CD127low/- Regulatory T-Cells in Different Stages of Psoriatic Arthritis Patients.

Psoriatic arthritis (PsA) is a systemic auto-immune condition characterized by diverse and distinctive inflammation, affecting both musculoskeletal and extra-articular systems. This study aims to investigate the role of regulatory T-cells (Tregs), specifically the CD4+CD25+/high CD127-/low subset, in PsA pathogenesis, and their potential as biomarkers and therapeutic targets. In a case-control study involving 40 PsA patients and 25 healthy individuals, CD4+ CD25+/high CD127-/low Tregs were analyzed in peripheral blood mononuclear cells (PBMCs) using flow cytometry. Disease activity was assessed using the Disease Activity in Psoriatic Arthritis (DAPSA) score. We observed a significant positive correlation between Treg levels and the DAPSA score (P = 0.02) in non-treated PsA patients. Additionally, patient age showed a significant positive correlation with erythrocyte sedimentation rate in the same group (P = 0.04), emphasizing the potential influence of Tregs on disease activity and age-related effects on inflammatory markers in PsA. While not revealing significant differences in Treg populations, our research underscores the importance of considering specific Treg subsets in PsA. These subsets may respond differently to disease micro-environments and treatments, affecting disease progression. This study contributes to the broader comprehension of immune dysregulation in auto-immune diseases and suggests that further investigation into Treg subsets' function and count is warranted. Such insights may lead to more tailored therapeutic approaches for PsA patients.

Helicobacter pylori infection and associated risk factors among HIV-positive and HIV-negative individuals in Northern Ethiopia

BackgroundH. pylori infection is a common bacterial infection worldwide, but its prevalence varies widely between different regions and populations. The objective of this study was to determine the prevalence of H. pylori infection and associated risk factors among HIV-positive and HIV-negative individuals in northern Ethiopia. MethodsA cross-sectional study was conducted from June to September 2020 in four randomly selected health facilities located in the Tigray region of Ethiopia. A total of 463 study participants were enrolled, of whom 288 were HIV-positive and 175 were HIV-negative individuals. H. pylori stool antigen tests were performed to detect H. pylori infection. Additionally, CD4+ T cell counts were measured from only a certain number of participants. ResultsThe overall prevalence of H. pylori infection among enrolled study participants was 39.7 %. Notably, the H. pylori infection rate was significantly higher in HIV-positive patients (43.4 %) compared to HIV-negative individuals (33.7 %); χ2 = 4.27, p = 0.039. Higher H. pylori prevalence was observed in participants with higher CD4+ T cell counts in both HIV-positive and HIV-negative individuals. Khat chewing habit, education, and monthly income levels were significantly associated with H. pylori infection in HIV-negative individuals, while the association between Body mass index (BMI) and H. pylori infection was observed in HIV-positive patients, but not HIV-negative individuals. ConclusionThis study demonstrates a higher prevalence of H. pylori infection in HIV-positive patients compared to HIV-negative individuals, emphasizing the importance of comprehensive diagnostics, patient care, and management of H. pylori infection in HIV-positive individuals.

Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study

BackgroundIn non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and...

Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma

Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) – inflamed, excluded, and desert – has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: POLE mutant (POLE), mismatch repair deficient (MMRd), TP53 mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) POLE, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and POLE (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.

Trametinib Sensitivity is Defined by a Myeloid Differentiation Profile in Acute Myeloid Leukemia.

Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML. We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response. We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification. Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.

Impact of “day 90” CD4+ T cells on clinical outcomes in children with relapsed/refractory acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

BackgroundThe severity of complications after hematopoietic stem cell transplantation (HSCT) is dictated by the degree of immune reconstitution. However, the connection between immune reconstitution and the prognosis of pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. Therefore, the aim of this study was to evaluate the impact of lymphocyte subsets in children diagnosed with refractory or relapsed acute myeloid leukemia (R/R-AML) after allo-HSCT. MethodsWe retrospectively investigated the prognosis and lymphocyte subsets at d 90 (D90) post-allo-HSCT in 130 children diagnosed with R/R-AML between September 2019 and October 2022 at the Children's Hospital of Soochow University. Lymphocyte subgroups were assessed by flow cytometric analysis on D90 and compared among human leukocyte antigen (HLA)-matched sibling donor HSCT (MSD) (n = 14), haploidentical donor HSCT (n = 94), and HLA-matched unrelated donor HSCT (n = 22) groups. The associations between the counts and frequencies of lymphocyte subgroups and prognosis were assessed. ResultsIn the MSD group, CD4+ T cell frequency and count were the highest (P < 0.001). Among the examined lymphocyte subsets, a lower proportion of CD4+ T cells (<14.535 %) at D90 correlated with a higher risk of cytomegalovirus infection (P = 0.002). A higher CD4+ T cell count (>121.39/μL) at D90 after HSCT was the single predictor of a lower fatality risk across all lymphocyte subgroups (univariate: P = 0.038 cut-off: 121.39/μL; multivariate: P = 0.036). No association with relapse was observed. ConclusionsCD4+ T cell count may be used to identify pediatric patients with R/R-AML with a greater mortality risk early after HSCT.

A comprehensive landscape analysis of autophagy in cancer development and drug resistance.

Autophagy plays important roles in cancer progression and therapeutic resistance, and the autophagy underlying the tumor pathogenesis and further mechanisms of chemoresistance emergence remains unknown. In this study, via the single-sample gene set enrichment analysis (ssGSEA) method, an autophagy 45-gene list was identified to evaluate samples' autophagy activity, verified through six GEO datasets with a confirmed autophagy phenotype. It was further utilized to distinguish tumors into autophagy score-high and score-low subtypes, and analyze their transcriptome landscapes, including survival analysis, correlation analysis of autophagy- and resistance-related genes, biological functional enrichment, and immune- and hypoxia-related and genomic heterogeneity comparison, in TCGA pan-cancer datasets. Furthermore, we performed an analysis of autophagy status in breast cancer chemoresistance combined with multiple GEO datasets and in vitro experiments to validate the mechanisms of potential anticancer drugs for reversing chemoresistance, including CCK-8 cell viability assays, RT-qPCR, and immunofluorescence. The 45-gene list was used to identify autophagy score-high and score-low subtypes and further analyze their multi-dimensional features. We demonstrated that cancer autophagy status correlated with significantly different prognoses, molecular alterations, biological process activations, immunocyte infiltrations, hypoxia statuses, and specific mutational processes. The autophagy score-low subtype displayed a more favorable prognosis compared with the score-high subtype, associated with their immune-activated features, manifested as high immunocyte infiltration, including high CD8+T, Tfh, Treg, NK cells, and tumor-associated macrophages M1/M2. The autophagy score-low subtype also showed a high hypoxia score, and hypoxic tumors showed a significantly differential prognosis in different autophagy statuses. Therefore, "double-edged" cell fates triggered by autophagy might be closely correlated with the immune microenvironment and hypoxia induction. Results demonstrated that dysregulated autophagy was involved in many cancers and their therapeutic resistance and that the autophagy was induced by the resistance-reversing drug response, in five breast cancer GEO datasets and validated by in vitro experiments. In vitro, dihydroartemisinin and artesunate could reverse breast cancer doxorubicin resistance, through inducing autophagy via upregulating LC3B and ATG7. Our study provided a comprehensive landscape of the autophagy-related molecular and tumor microenvironment patterns for cancer progression and resistance, and highlighted the promising potential of drug-induced autophagy in the activation of drug sensitivity and reversal of resistance.

Immunological and virological response to fostemsavir in routine US clinical care: An OPERA cohort study.

Fostemsavir is a novel attachment inhibitor used with other antiretrovirals in heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. Real-world immunological and virological responses were assessed in individuals starting fostemsavir in the OPERA cohort. Among adults with HIV-1 starting fostemsavir between 2 July 2020 and 1 September 2022, 6-month and 12-month changes in CD4 T-cell count and CD4%, and maintenance/achievement of viral load (VL) <50 copies/mL were described and stratified by baseline VL (suppressed: <50 copies/mL; viraemic: ≥50 copies/mL) and CD4 count (high: ≥350 cells/μL; low: <350 cells/μL). Of 182 individuals starting fostemsavir, 64% were viraemic (34% low CD4, 30% high CD4) and 36% were suppressed (16% low CD4, 20% high CD4). The suppressed/low CD4 group had the largest median increases in CD4 count (6-month: 30 cells/μL [interquartile range {IQR} 9-66], 12-month: 66 cells/μL [IQR 17-125]), and CD4% (6-month: 1.0% [IQR -0.3-2.8], 12-month: 1.9% [IQR 1.3-3.9]). Regardless of baseline VL, those with a high baseline CD4 count experienced a greater variability in immunological response than those with low CD4 counts (12-month standard deviation range 172-231 cells/μL vs. 69-90 cells/μL). VL <50 copies/mL was maintained in most suppressed individuals; nearly half of the viraemic/high CD4 group and a third of the viraemic/low CD4 group achieved a VL <50 copies/mL at either timepoint. After 6 or 12 months of fostemsavir use, virological response was low in viraemic individuals, although most suppressed individuals did maintain suppression. While immunological response varied across individuals, virologically suppressed HTE individuals with low CD4 counts may benefit from immunological improvements with fostemsavir.