Functional genomics identifies N-acetyllactosamine extension of complex N-glycans as a mechanism to evade lysis by natural killer cells.

Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity.

Response to Bruton's tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy.

Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer, presenting a challenge for precision medicine. Bruton's tyrosine kinase (BTK) inhibitors block B cell receptor (BCR) signaling and are particularly effective in certain molecular subtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB. The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B, and in the innate immune adapter, MYD88, typically resists chemotherapy but responds exceptionally to BTK inhibitors.

The Flow Cytometric Analysis of Peripheral Blood Lymphocytes and Expression of HLA II Molecules in Lymphocyte During Acute Rejection After Renal Transplantation.

Objective: To investigate the changes in the proportion of peripheral blood lymphocytes and the expression of HLA II molecules in lymphocytes during acute rejection after renal transplantation.

Methods: Thirty-five patients who had undergone renal transplantation were selected. Eighteen patients with clinical and pathological confirmed acute rejection were selected as the test group, and twelve patients without clinical acute rejection symptoms were selected as the control group.

NK Cells Equipped With a Chimeric Antigen Receptor That Overcomes Inhibition by HLA Class I for Adoptive Transfer of CAR-NK Cells.

Dominant inhibitory receptors for HLA class I (HLA-I) endow NK cells with high intrinsic responsiveness, a process termed licensing or education, but hinder their ability to kill HLA-I tumor cells. Cancer immunotherapy with adoptive transfer of NK cells must overcome inhibitory signals by such receptors to promote elimination of HLA-I tumor cells. As proof of concept, we show here that a chimeric antigen receptor (CAR) can be engineered to overcome inhibition by receptors for HLA-I and to promote lysis of HLA-I tumor cells by CAR-NK cells.

CRISPR Screen to Identify Factors that Render Tumor Cells Sensitive or Resistant to Killing by NK Cells.

Natural killer (NK) cells are an important component of the cancer immune surveillance system. They are regulated by germline-encoded receptors that activate and inhibit their effector function, such as secretion of cytokines and direct lysis of tumor cells and virus-infected cells. Without the need to be primed by prior exposure to tumor antigen, NK cells can detect ligands expressed on tumor cells and selectively kill these cells.

SKAP interacts with Aurora B to guide end-on capture of spindle microtubules via phase separation.

Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent studies show that mitotic motor CENP-E cooperates with SKAP and forms a link between kinetochore core MIS13 complex and spindle microtubule plus-ends to achieve accurate chromosome alignment in mitosis. However, it remains elusive how SKAP regulates kinetochore attachment from lateral association to end-on attachment during metaphase alignment.

An engineered IL-2 partial agonist promotes CD8 T cell stemness.

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells and lower therapeutic efficacy, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial.

Optimized photocatalytic regeneration of adsorption-photocatalysis bifunctional composite saturated with Methyl Orange.

Photo-responsive adsorption-photocatalysis nanocomposites are generally used in water and wastewater decontamination; however, the prolonged adsorption capacity of composites and the role of adsorption in concomitant photocatalysis are typically neglected. These composites can be regenerated under light irradiation as their adsorption capacity decreases. Herein, a novel adsorption-photocatalysis bifunctional nanocomposite, Bi-doped TiO supported on powdered activated carbon (BiO/TiO/PAC), was prepared using the sol-impregnation-hydrothermal procedure.

Genome-Wide CRISPR Screen Reveals Cancer Cell Resistance to NK Cells Induced by NK-Derived IFN-γ.

The anti-leukemia activity of NK cells helps prevent relapse during hematopoietic stem cell transplantation (HSCT) in leukemia patients. However, the factors that determine the sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well-established. Here, we performed a genome-wide CRISPR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate the vulnerability of leukemia cells to killing by primary human NK cells.

Inhibition-Resistant CARs for NK Cell Cancer Immunotherapy.

The promise of natural killer (NK) cells as effectors in cancer cellular therapy is limited by their expression of dominant inhibitory receptors for human leukocyte antigen (HLA) class I. Here, we discuss how chimeric antigen receptors (CARs) engineered to override inhibitory signaling might boost NK cell antitumor responses, independently of blockade of NK cell inhibitory receptors.

CD28 Homolog Is a Strong Activator of Natural Killer Cells for Lysis of B7H7 Tumor Cells.

The CD28-B7 family of receptor-ligand pairs regulates lymphocyte responses through costimulation and coinhibition. It includes checkpoint inhibitors, such as PD-1, which limit antitumor and antivirus T-cell responses. CD28 homolog (CD28H) and B7H7 have been identified as a receptor-ligand pair in this family, which has costimulatory activity in T cells.

LRIF1 interacts with HP1α to coordinate accurate chromosome segregation during mitosis.

Heterochromatin protein 1α (HP1α) regulates chromatin specification and plasticity during cell fate decision. Different structural determinants account for HP1α localization and function during cell division cycle. Our earlier study showed that centromeric localization of HP1α depends on the epigenetic mark H3K9me3 in interphase, while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors.

The Microtubule Plus End Tracking Protein TIP150 Interacts with Cortactin to Steer Directional Cell Migration.

Cell migration is orchestrated by dynamic interactions of microtubules with the plasma membrane cortex. How these interactions facilitate these dynamic processes is still being actively investigated. TIP150 is a newly characterized microtubule plus end tracking protein essential for mitosis and entosis (Ward, T.

Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation.

Faithful segregation of chromosomes in mammalian cells requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying cyclin-dependent kinase 1 (CDK1) activation, which triggers mitotic entry, have been extensively studied, the regulatory mechanisms that couple CDK1-cyclin B activity to chromosome stability are not well understood. Here, we identified a signaling axis in which Aurora B activity is modulated by CDK1-cyclin B via the acetyltransferase TIP60 in human cell division.

Signaling Scaffold Protein IQGAP1 Interacts with Microtubule Plus-end Tracking Protein SKAP and Links Dynamic Microtubule Plus-end to Steer Cell Migration.

Cell migration is orchestrated by dynamic interaction of microtubules with the plasma membrane cortex. However, the regulatory mechanisms underlying the cortical actin cytoskeleton and microtubule dynamics are less characterized. Our earlier study showed that small GTPase-activating proteins, IQGAPs, regulate polarized secretion in epithelial cells (1).

Mitotic regulator SKAP forms a link between kinetochore core complex KMN and dynamic spindle microtubules.

Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent study shows that mitotic motor CENP-E cooperates with SKAP to orchestrate an accurate chromosome movement in mitosis. However, it remains elusive how kinetochore core microtubule binding activity KMN (KNL1-MIS12-NDC80) regulates microtubule plus-end dynamics.

CENP-E kinesin interacts with SKAP protein to orchestrate accurate chromosome segregation in mitosis.

Mitotic chromosome segregation is orchestrated by the dynamic interaction of spindle microtubules with the kinetochore. Although previous studies show that the mitotic kinesin CENP-E forms a link between attachment of the spindle microtubule to the kinetochore and the mitotic checkpoint signaling cascade, the molecular mechanism underlying dynamic kinetochore-microtubule interactions in mammalian cells remains elusive. Here, we identify a novel interaction between CENP-E and SKAP that functions synergistically in governing dynamic kinetochore-microtubule interactions.