Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies

Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy

Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans.The application of natural cytokines in clinical studies has not been clearly established,and there are often problems associated with toxicity or lack of efficacy.The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells.With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions,artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach.Engineered cytokines are designed to selectively target cells.Herein,the theoretical and experimental evidence of cytokine engineering is reviewed,and the“supercytokines”resulting from structural enhancement and the“immunocytokines”generated by antibody fusion are described.Finally,the“engager cytokines”formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.

Void fraction measurement of bubble and slug flow in a small channel using the multivision technique

Using the multivision technique, a new void fraction measurement method was developed for bubble and slug flow in a small channel. The multivision system was developed to obtain images of the two-phase flow in two perpendicular directions. The obtained images were processed--using image segmentation, image subtraction, Canny edge detection, binarization, and hole filling-to extract the phase boundaries and information about the bubble or slug parameters, With the extracted information, a new void fraction measurement model was developed and used to determine the void fraction of the two-phase flow. The proposed method was validated experimentally in horizontal and vertical channels with different inner diameters of 2.1, 2.9, and 4.0 mm, The proposed method of measuring the void fraction has better performance than the methods that use images acquired in only one direction, with a maximum absolute difference between the measured and reference values of less than 6%.

Transcriptomic characteristics and impaired immune function of patients who retest positive for SARS-CoV-2 RNA

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,has become a global public health crisis.Some patients who have recovered from COVID-19 subsequently test positive again for SARS-CoV-2 RNA after discharge from hospital.How such retest-positive(RTP)patients become infected again is not known.In this study,30 RTP patients,20 convalescent patients,and 20 healthy controls were enrolled for the analysis of immunological characteristics of their peripheral blood mononuclear cells.We found that absolute numbers of CD4^(+)T cells,CD8^(+)T cells,and natural killer cells were not substantially decreased in RTP patients,but the expression of activation markers on these cells was significantly reduced.The percentage of granzyme B-producing T cells was also lower in RTP patients than in convalescent patients.Through transcriptome sequencing,we demonstrated that high expression of inhibitor of differentiation 1(ID1)and low expression of interferon-induced transmembrane protein 10(IFITM10)were associated with insufficient activation of immune cells and the occurrence of RTP.These findings provide insight into the impaired immune function associated with COVID-19 and the pathogenesis of RTP,which may contribute to a better understanding of the mechanisms underlying RTP.

Increased expression of adenosine A3 receptor in tumor-infiltrating natural killer cells

Checkpoint blockade on lymphocyte surfaces has revolutionizedcancer treatment.ln particular,blockade of programmed celldeath protein-1 by therapeutic antibodies is remarkably effectiveto reactivate T cells for the treatment of several cancer types.^(1,2).lmmune checkpoint inhibitors that promote natural killer(NK)celleffector function have also recently demonstrated significantefficacy.^(3,4)Notably however,one of the main challenges of theseclinical immunotherapies is that the majority of patients areresistant to immune checkpoint inhibitors^(5).One practicalapproach to address this is identifying novel molecular targetsand manipulating them to enhance antitumor immunity.