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Scientific Reports Jul 2024The monocyte distribution width (MDW) has emerged as a promising biomarker for accurate and early identification of patients with potentially life-threatening...
Understanding the value of monocyte distribution width (MDW) in acutely ill medical patients presenting to the emergency department: a prospective single center evaluation.
The monocyte distribution width (MDW) has emerged as a promising biomarker for accurate and early identification of patients with potentially life-threatening infections. Here we tested the diagnostic performance of MDW in adult patients requiring hospital admission for community-acquired infections and sepsis, evaluated sources of heterogeneity in the estimates of diagnostic accuracy, and assessed the meaning of MDW in a patient population presenting to the emergency department (ED) for acute non-infectious conditions. 1925 consecutive patients were categorized into three groups: non-infection (n = 1507), infection (n = 316), and sepsis/septic shock (n = 102). Diagnostic performance for infection or sepsis of MDW alone or in combination with components of SOFA was tested using AUC of ROC curves, sensitivity, and specificity. The relationship between MDW and different pathogens as well as the impact of non-infectious conditions on MDW values were explored. For the prediction of infection, the AUC/ROC of MDW (0.84) was nearly overlapping that of procalcitonin (0.83), and C-reactive protein (0.89). Statistical optimal cut-off value for MDW was 21 for predicting infection (sensitivity 73%, specificity 82%) and 22 for predicting sepsis (sensitivity 79%, specificity 83%). The best threshold to rule out infection was MDW ≤ 17 (NPV 96.9, 95% CI 88.3-100.0), and ≤ 18 (NPV 99.5, 95% CI 98.3-100.0) to rule out sepsis. The combination of MDW with markers of organ dysfunction (creatinine, bilirubin, platelets) substantially improved the AUC (0.96 (95% CI 0.94-0.97); specificity and sensitivity of 88% and 94%, respectively). In conclusion, MDW has a good diagnostic performance in diagnosing infection and sepsis in patients presenting in ED. Its use as an infection marker even increases when combined with other markers of organ dysfunction. Understanding the impact of interactions of non-infectious conditions and comorbidities on MDW and its diagnostic accuracy requires further elucidation.
Topics: Humans; Emergency Service, Hospital; Male; Female; Middle Aged; Prospective Studies; Aged; Sepsis; Monocytes; Biomarkers; Adult; ROC Curve; Acute Disease; Aged, 80 and over; Community-Acquired Infections; Sensitivity and Specificity
PubMed: 38956252
DOI: 10.1038/s41598-024-65883-8 -
Nature Communications Jul 2024Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential...
Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses.
Topics: Receptors, Antigen, T-Cell; Single-Cell Analysis; Humans; SARS-CoV-2; COVID-19; Transcriptome; T-Lymphocytes; Gene Expression Profiling; Antigens, Viral
PubMed: 38956082
DOI: 10.1038/s41467-024-49806-9 -
Nature Communications Jul 2024The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which...
The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which have been predominantly conducted in males in the United States and Europe living with HIV-1 subtype B, have revealed that most proviruses that persist during antiretroviral therapy (ART) are defective. In contrast, less is known about proviral landscapes in females with non-B subtypes, which represents the largest group of individuals living with HIV-1. Here, we analyze genomic DNA from resting CD4+ T-cells from 16 female and seven male Ugandans with HIV-1 receiving suppressive ART (n = 23). We perform near-full-length proviral sequencing at limiting dilution to examine the proviral genetic landscape, yielding 607 HIV-1 subtype A1, D, and recombinant proviral sequences (mean 26/person). We observe that intact genomes are relatively rare and clonal expansion occurs in both intact and defective genomes. Our modification of the primers and probes of the Intact Proviral DNA Assay (IPDA), developed for subtype B, rescues intact provirus detection in Ugandan samples for which the original IPDA fails. This work will facilitate research on HIV-1 persistence and cure strategies in Africa, where the burden of HIV-1 is heaviest.
Topics: Humans; HIV-1; Proviruses; HIV Infections; Male; Female; Genome, Viral; CD4-Positive T-Lymphocytes; Adult; DNA, Viral; Uganda; Viral Load; Anti-HIV Agents
PubMed: 38956017
DOI: 10.1038/s41467-024-48985-9 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jun 2024This study aims to explore the diagnostic value of inflammation-related genes in peripheral blood mononuclear cells in bronchopulmonary dysplasia (BPD). By using...
This study aims to explore the diagnostic value of inflammation-related genes in peripheral blood mononuclear cells in bronchopulmonary dysplasia (BPD). By using bioinformatics analysis, three datasets including GSE32472, GSE125873, and GSE220135, which contain whole-genome expression profile data of 251 neonates, were included. The GSE32472 dataset was used as a training dataset to detect differentially expressed genes between non-BPD and BPD neonates in peripheral blood mononuclear cells. The gene enrichment analysis (GSEA) was used to detect the pathway enrichment of up-regulated genes in BPD newborns. The main regulatory factors analysis (MRA) algorithm was used to filter the main regulatory genes in the inflammation-related pathway (GO:0006954). After obtaining the main regulatory genes, the expression of the main regulatory genes in the GSE32472, GSE125873, and GSE220135 datasets was detected. Through the logistic regression model, risk scoring was conducted for neonates, and the risk scores of non-BPD and BPD neonates were compared. Lastly, the classification performance of the model was evaluated using the area under the curve (AUC). The results showed that compared with non-BPD neonates, there were 486 up-regulated genes and 433 down-regulated genes in the peripheral blood mononuclear cells of BPD neonates. The inflammation-related pathway was highly enriched in the up-regulated genes. Ultimately, phospholipase C beta 1 (PLCB1), nidogen 1 (NID1), serum response factor binding protein 1 (SRFBP1), centrosomal protein 72 (CEP72), excision repair cross complementation group 6 like (ERCC6L), and peptidylprolyl isomerase like 1 (PPIL1) were identified as the main regulatory genes. The prediction model's calculation formula for risk score was PLCB1×0.26+NID1×0.97+SRFBP1×1.58+CEP72×(-0.36)+ERCC6L×2.14+PPIL1×0.67. The AUCs in the GSE32472 test dataset, GSE125873 dataset, and GSE220135 dataset were 0.88, 0.86, and 0.89, respectively. This prediction model could distinguish between non-BPD and BPD neonates. In conclusion, the prediction model based on inflammation-related pathway genes has a certain diagnostic value for BPD.
Topics: Humans; Bronchopulmonary Dysplasia; Infant, Newborn; Inflammation; Leukocytes, Mononuclear; Gene Expression Profiling; Computational Biology
PubMed: 38955739
DOI: 10.3760/cma.j.cn112150-20231012-00257 -
Journal For Immunotherapy of Cancer Jul 2024Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient...
BACKGROUND
Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient subgroups remain non-responsive underscoring the necessity for combinational therapies harnessing additional immune cells. Natural killer (NK) cells are emerging tools for cancer therapy. However, only subpopulations of NK cells that are differentially controlled by inhibitory receptors exert reactivity against particular cancer types. How to leverage the complete anti-tumor potential of all NK cell subsets without favoring the emergence of NK cell-resistant tumor cells remains unresolved.
METHODS
We performed a genome-wide CRISPR/Cas9 knockout resistance screen in melanoma cells in co-cultures with human primary NK cells. We comprehensively evaluated factors regulating tumor resistance and susceptibility by focusing on NK cell subsets in an allogenic setting. Moreover, we tested therapeutic blocking antibodies currently used in clinical trials.
RESULTS
Melanoma cells deficient in antigen-presenting or the IFNγ-signaling pathways were depleted in remaining NK cell-co-cultured melanoma cells and displayed enhanced sensitivity to NK cells. Treatment with IFNγ induced potent resistance of melanoma cells to resting, IL-2-cultured and ADCC-activated NK cells that depended on required for the expression of both classical and non-classical MHC-I. IFNγ-induced expression of HLA-E mediated the resistance of melanoma cells to the NKG2A KIR and partially to the NKG2A KIR NK cell subset. The expression of classical MHC-I by itself was sufficient for the inhibition of the NKG2A KIR, but not the NKG2A KIR NK cell subset. Treatment of NK cells with monalizumab, an NKG2A blocking mAb, enhanced the reactivity of a corresponding subset of NK cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, blocking KIR3DL1, was required to restore cytotoxicity of all NK cell subsets against IFNγ-induced resistant tumor cells in melanoma and tumors of different origins.
CONCLUSION
Our data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets.
Topics: Humans; Killer Cells, Natural; Interferon-gamma; Melanoma; Cell Line, Tumor; Coculture Techniques
PubMed: 38955423
DOI: 10.1136/jitc-2024-009410 -
Journal For Immunotherapy of Cancer Jul 2024Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed "cold" based on lack of T cell infiltration...
BACKGROUND
Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed "cold" based on lack of T cell infiltration show reduced potential for CPI therapy. Cancer vaccines may overcome the inadequacy of existing T cells by inducing the needed antitumor T cell response to synergize with CPIs and overcome resistance.
METHODS
CT26 and TC1 tumor cells were injected subcutaneously into mice. Mice were treated with combinations of CPIs alone or a cancer vaccine specific to the tumor antigen E7 present in TC1 cells. CPIs for the TC1 model were selected because of immunophenotyping TC1 tumors. Antitumor and protumor immunity, tumor size and survival, sequence and timing of vaccine and CPI administration, and efficacy of treatment in young and aged mice were probed.
RESULTS
While "hot" CT26 tumors are treatable with combinations of second-generation CPIs alone or with anti-TGFβ, "cold" TC1 tumor reduction requires the synergy of a tumor-antigen-specific vaccine in combination with two CPIs, anti-TIGIT and anti-PD-L1, predicted by tumor microenvironment (TME) characterization. The synergistic triple combination delays tumor growth better than any pairwise combination and improves survival in a CD8+T cell-dependent manner. Depletion of CD4+T cells improved the treatment response, and depleting regulatory T cells (Treg) revealed Tregs to be inhibiting the response as also predicted from TME analysis. We found the sequence of CPI and vaccine administration dictates the success of the treatment, and the triple combination administered concurrently induces the highest E7-specific T cell response. Contrary to young mice, in aged mice, the cancer vaccine alone is ineffective, requiring the CPIs to delay tumor growth.
CONCLUSIONS
These findings show how pre-existing or vaccine-mediated de novo T cell responses can both be amplified by and facilitate synergistic CPIs and Treg depletion that together lead to greater survival, and how analysis of the TME can help rationally design combination therapies and precision medicine to enhance clinical response to CPI and cancer vaccine therapy.
Topics: Animals; Cancer Vaccines; Mice; Immune Checkpoint Inhibitors; Tumor Microenvironment; T-Lymphocytes, Regulatory; Female; Cell Line, Tumor; Humans
PubMed: 38955422
DOI: 10.1136/jitc-2024-008970 -
Journal For Immunotherapy of Cancer Jul 2024Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood...
BACKGROUND
Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.
METHODS
We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.
RESULTS
Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.
CONCLUSION
Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.
Topics: Animals; Mice; Antigens, CD19; Interleukin-15; Immunotherapy, Adoptive; Humans; Disease Models, Animal; Cell Line, Tumor; Female; Interleukin-15 Receptor alpha Subunit; Receptors, Chimeric Antigen; Lymphoma; Mice, Inbred BALB C; T-Lymphocytes
PubMed: 38955421
DOI: 10.1136/jitc-2023-008572 -
PloS One 2024Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized...
INTRODUCTION
Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics.
METHODS
Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma.
RESULTS
CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated.
CONCLUSIONS
PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.
Topics: Humans; Pancreatic Neoplasms; Male; Female; Adenocarcinoma; Middle Aged; Aged; Tumor Microenvironment; B7-H1 Antigen; HLA-G Antigens; Programmed Cell Death 1 Ligand 2 Protein; Prognosis; CD8-Positive T-Lymphocytes; Adult; T-Lymphocytes, Regulatory; Aged, 80 and over; Macrophages
PubMed: 38954689
DOI: 10.1371/journal.pone.0305648 -
Journal of Clinical Immunology Jul 2024Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described...
BACKGROUND
Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome.
OBJECTIVES
To treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation.
METHODS
Two patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab.
RESULTS
Combination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12-36 months following treatment initiation.
CONCLUSION
Lymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma.
Topics: Humans; Thymoma; Female; Immunomodulation; Male; Rituximab; Autoantibodies; Middle Aged; Thymus Neoplasms; Pneumonia; Autoimmune Diseases; Adult; Azathioprine; B-Lymphocytes; Treatment Outcome; T-Lymphocytes
PubMed: 38954150
DOI: 10.1007/s10875-024-01760-3 -
Cancer Immunology, Immunotherapy : CII Jul 2024Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo)...
BACKGROUND
Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment.
METHODS
A total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan-Meier analyses).
RESULTS
Healthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADRCD11cCD14CD68CD163CD33) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001).
CONCLUSION
A hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.
Topics: Humans; Female; Vulvar Neoplasms; Prognosis; Carcinoma, Squamous Cell; Biomarkers, Tumor; Monocytes; Middle Aged; Aged; Lymphocytes, Tumor-Infiltrating; Adult; Aged, 80 and over
PubMed: 38954042
DOI: 10.1007/s00262-024-03755-w