Targeting of the CD161 inhibitory receptor enhances T-cell-mediated immunity against hematological malignancies.

ABSTRACT: The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in multiple human solid tumor types, and its ligand, CLEC2D, is expressed by both tumor cells and infiltrating myeloid cells. Here, we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia revealed that CLEC2D messenger RNA was most abundant in hematological malignancies, including B-cell and T-cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We, therefore, used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and nonhuman primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T-cell function, including cytotoxicity, cytokine production, and proliferation, against B-cell lines originating from patients with acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T-cell-mediated immunity, resulting in a significant survival benefit. Single cell RNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-residency program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human mAbs, thus, represent potential immunotherapy agents for hematological malignancies.

[Relationship between accumulation of autotoxins and soil fertility factors under long-term continuous cropping of cucumber in solar greenhouse]. / æ—¥å ‰æ¸©å®¤é»„ç“œé•¿æœŸè¿žä½œè‡ªæ¯’ç‰©è´¨ç´¯ç§¯ä¸ŽåœŸå£¤è‚¥åŠ›å› å­çš„å ³ç³».

In this study, we investigated the effects of long-term continuous cucumber cropping on phenolic acids in rhizosphere soil, as well as their link to soil chemical characteristics, enzyme activities, and microbiological activities, using rhizosphere soil from the 2nd, 6th, 10th, 14th, 18th, 20th, 24th, and 26th round of cucumber cultivation in solar greenhouse. The results showed that contents of phenolic acids increased significantly with increasing continuous cropping rounds. The increase amount per round of total phenolic acid was significantly higher in the early stage (0-2 rounds) and late stage (20-26 rounds) than middle stage (10-14 rounds) of continuous cropping. Soil nutrient contents were enriched, while invertase enzyme activity and microbial activities were decreased. Redundancy analysis showed that organic matter, total phosphorus, total nitrogen, available nitrogen, microbial biomass carbon and microbial metabolic entropy were main soil fertility factors correlating with the accumulation of phenolic acids. Results of structural equation model showed that soil phosphorus enrichment directly led to the accumulation of phenolic acids, and that nitrogen enrichment indirectly facilitated the accumulation of phenolic acids by altering the activity of microorganisms. As a result, proper nitrogen and phosphorus fertilizers application would reduce the accumulation of phenolic acids and alleviate the cucumber continuous cropping obstacles.

A vaccine targeting resistant tumours by dual T cell plus NK cell attack.

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.

Molecular transitions in early progenitors during human cord blood hematopoiesis.

Hematopoietic stem cells (HSCs) give rise to diverse cell types in the blood system, yet our molecular understanding of the early trajectories that generate this enormous diversity in humans remains incomplete. Here, we leverage Drop-seq, a massively parallel single-cell RNA sequencing (scRNA-seq) approach, to individually profile 20,000 progenitor cells from human cord blood, without prior enrichment or depletion for individual lineages based on surface markers. Our data reveal a transcriptional compendium of progenitor states in human cord blood, representing four committed lineages downstream from HSC, alongside the transcriptional dynamics underlying fate commitment. We identify intermediate stages that simultaneously co-express "primed" programs for multiple downstream lineages, and also observe striking heterogeneity in the early molecular transitions between myeloid subsets. Integrating our data with a recently published scRNA-seq dataset from human bone marrow, we illustrate the molecular similarity between these two commonly used systems and further explore the chromatin dynamics of "primed" transcriptional programs based on ATAC-seq. Finally, we demonstrate that Drop-seq data can be utilized to identify new heterogeneous surface markers of cell state that correlate with functional output.

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.

Human dendritic cells (DCs) are derived from distinct circulating precursors that are precommitted to become CD1c+ or CD141+ DCs.

In humans, conventional dendritic cells (cDCs) exist as two unique populations characterized by expression of CD1c and CD141. cDCs arise from increasingly restricted but well-defined bone marrow progenitors that include the common DC progenitor that differentiates into the pre-cDC, which is the direct precursor of cDCs. In this study, we show that pre-cDCs in humans are heterogeneous, consisting of two distinct populations of precursors that are precommitted to become either CD1c+ or CD141+ cDCs. The two groups of lineage-primed precursors can be distinguished based on differential expression of CD172a. Both subpopulations of pre-cDCs arise in the adult bone marrow and can be found in cord blood and adult peripheral blood. Gene expression analysis revealed that CD172a+ and CD172a- pre-cDCs represent developmentally discrete populations that differentially express lineage-restricted transcription factors. A clinical trial of Flt3L injection revealed that this cytokine increases the number of both CD172a- and CD172a+ pre-cDCs in human peripheral blood.

[Reconstruction of pelvic ring with minimally invasive plate fixation].

OBJECTIVE: To investigate the effectiveness of minimally invasive plate fixation in treatment of unstable pelvic fractures. METHODS: Between May 2006 and December 2009, 21 patients with unstable pelvic fractures were treated. There were 13 males and 8 females with an average age of 39 years (range, 21-66 years). The causes of injury included traffic accident in 9 cases, falling from height in 6 cases, and heavy pound injury in 6 cases. The time from injury to hospitalization was 1 to 4 hours with an average of 2.8 hours. According to Tile's classification, there were 12 cases of type B and 9 cases of type C. After admission, bone traction and exo fixation were performed, and minimally invasive plate fixation was given at 5-24 days after injury. RESULTS: All incisions healed by first intention, and no complications of nerve and vessel injuries occurred. According to the reduction criteria of Matta radiography, anatomic reduction was achieved in 16 cases, satisfactory reduction in 4 cases, and fair reduction in 1 case. All patients were followed up 12 months. The X-ray films showed all fractures healed at 2-4 months (mean, 2.6 months). According to Majeed clinical evaluation, the results were excellent in 12 cases, good in 7 cases, and fair in 2 cases. CONCLUSION: Minimally invasive plate fixation can provide effective fixation, reconstruct pelvic ring, and reduce perioperative complications in the treatment of unstable pelvic fractures.