A pan-cancer single-cell panorama of human natural killer cells.

Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the tumor microenvironment, we perform integrative single-cell RNA sequencing analyses on NK cells from 716 patients with cancer, covering 24 cancer types. We observed heterogeneity in NK cell composition in a tumor-type-specific manner. Notably, we have identified a group of tumor-associated NK cells that are enriched in tumors, show impaired anti-tumor functions, and are associated with unfavorable prognosis and resistance to immunotherapy. Specific myeloid cell subpopulations, in particular LAMP3+ dendritic cells, appear to mediate the regulation of NK cell anti-tumor immunity. Our study provides insights into NK-cell-based cancer immunity and highlights potential clinical utilities of NK cell subsets as therapeutic targets.

Virtual Evolution of HVEM Segment for Checkpoint Inhibitor Discovery.

Immune therapy has emerged as an effective treatment against cancers. Inspired by the PD-1/PD-L1 antibodies, which have achieved great success in clinical, other immune checkpoint proteins have drawn increasing attention in cancer research. B and T lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) are potential targets for drug development. The co-crystal structure of BTLA/HVEM have revealed that HVEM (26-38) fragment is the core sequence which directly involved on the interface. Herein, we conducted virtual evolution with this sequence by using saturation mutagenesis in silico and mutants with lower binding energy were selected. Wet-lab experiments confirmed that several of them possessed higher affinity with BTLA. Based on the best mutant of the core sequence, extended peptides with better efficacy were obtained. Furthermore, the mechanism of the effects of mutations was revealed by computational analysis. The mutated peptide discovered here can be a potent inhibitor to block BTLA/HVEM interaction and its mechanism may extend people's view on inhibitor discovery for the checkpoint pair.

BCAP Regulates Dendritic Cell Maturation Through the Dual-Regulation of NF-κB and PI3K/AKT Signaling During Infection.

The maturation of dendritic cells (DCs) is essential in adaptive immunity. B cell adapter for phosphoinositide 3-kinase (BCAP) has been shown a divergent activities in cell type dependent manner including B cells, NK cells, macrophages, and plasmacytoid DCs (pDCs), however, its role in conventional DCs (cDCs) remains unknown. Here, we report that BCAP negatively regulates Toll-like receptor-induced cDC maturation and inhibits cDCs from inducing antigen-specific T cell responses, thereby weakening the antibacterial adaptive immune responses of mice in a Listeria monocytogenes-infection model. Furthermore, we demonstrate that BCAP simultaneously modulates the activation of the NF-κB and PI3K/AKT signaling by dynamically interacting with, respectively, MyD88 and the p85α subunit of PI3K. Our study thus reveals non-redundant roles for BCAP in regulating cDC maturation and reveals a bilateral signal transduction mechanism.

Interleukin-33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development.

Increasing evidence suggests that IL-33 plays an important role in regulating tumor development. However, conflicting results, obtained from numerous studies, have highlighted the divergent functions of IL-33. The detailed mechanisms by which IL-33 modulates tumor development merit further investigation. Here, we report that IL-33 administration can effectively inhibit the development of pulmonary metastasis of breast cancer in a mouse. In our model, IL-33 promotes the production of TNF-α by macrophages, which increases IL-33 specific receptor (ST2) expression on natural killer (NK) cells and is pivotal in IL-33-induced NK cell activation. IL-33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+ T cells, which mediates the recruitment of NK cells to the tumor microenvironment. The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung. Our study reports a novel mechanism for the IL-33-meditated suppression of metastatic cancer and provides potential therapeutic strategies for targeting metastatic tumor.

MOZ Forms an Autoregulatory Feedback Loop with miR-223 in AML and Monocyte/Macrophage Development.

Monocytic leukemia zinc-finger protein (MOZ) has been found to form fusion proteins with many regulators in acute myeloid leukemia (AML). However, the molecular functions and underlying mechanism of MOZ in AML is not well understood. Here, clinical MOZ expression analysis combined with data integration from the TCGA and GEO databases indicated that a low level of MOZ was associated with poor prognosis. MOZ knockdown inhibited monocyte differentiation and increased resistance to chemotherapeutic drug-induced apoptosis in THP-1 or U937 cells. In addition, we found that genetic silencing of MOZ suppressed AP-1 and AKT activity in the context of lipopolysaccharide stimulation, resulting in diminished M1 activation of macrophages. We further showed that MOZ was a validated target of miR-223 and functioned as a repressor of miR-223 expression. Our study indicates that a molecular network involving MOZ and miR-223 contributes to the monocyte differentiation and polarization program, which is deregulated in AML.

STAT3 and NF-κB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer.

Tumour-induced dendritic cell (DC) dysfunction plays an important role in cancer immune escape. However, the underlying mechanisms are not yet fully understood, reflecting the lack of appropriate experimental models both in vivo and in vitro. In the present study, an in vitro study model for tumour-induced DC dysfunction was established by culturing DCs with pooled sera from multiple non-small cell lung cancer (NSCLC) patients. The results demonstrated that tumour-induced human monocyte-derived DCs exhibited systematic functional deficiencies. Transcriptomics analysis revealed that the expression of major functional cluster genes, including the MHC class II family, cytokines, chemokines, and co-stimulatory molecules, was significantly altered in tumour-induced DCs compared to that in control cells. Further examination confirmed that both NF-κB and STAT3 signalling pathways were simultaneously repressed by cancer sera, suggesting that the attenuated NF-κB and STAT3 signalling could be the leading cause of DC dysfunction in cancer. Furthermore, reversing the deactivated NF-κB and STAT3 signalling could be a strategy for cancer immunotherapy.