PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma.

Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging.

Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression.

Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant.

The immune checkpoint receptor PD-1 and its ligand, PD-L1, have emerged as key regulators of anti-tumor immunity in humans. Recently, we reported an ultra-high-affinity PD-1 mutant, termed high-affinity consensus (HAC) PD-1, which shows superior therapeutic efficacy in mice compared with antibodies. However, the molecular details underlying the action of this agent remain incompletely understood, and a molecular view of PD-1/PD-L1 interactions in general is only beginning to emerge.

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer.

Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment.

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.

Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells.

MicroRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas.

Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (B-NHL), which originates from germinal center (GC) B cells and harbors translocations deregulating v-myc avian myelocytomatosis viral oncogene homolog (MYC). A comparative analysis of microRNAs expressed in normal and malignant GC B cells identified microRNA 28 (miR-28) as significantly down-regulated in BL, as well as in other GC-derived B-NHL. We show that reexpression of miR-28 impairs cell proliferation and clonogenic properties of BL cells by modulating several targets including MAD2 mitotic arrest deficient-like 1, MAD2L1, a component of the spindle checkpoint whose down-regulation is essential in mediating miR-28-induced proliferation arrest, and BCL2-associated athanogene, BAG1, an activator of the ERK pathway.

RNAs with multiple personalities.

In the last decade, advances in sequencing technology and a renewed focus on the regulatory potential of RNA molecules have combined to stimulate an enormous expansion in the catalog of known eukaryotic RNAs. Beyond the sheer numerical diversity of RNA species, recent studies have begun to uncover hints of even greater functional complexity. An increasing number of RNA molecules, including those from classic, well-studied classes, have been found to act in previously unanticipated regulatory roles, or as substrate for the biogenesis of functionally distinct RNA molecules, or both.

A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response.

tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma.

Sequencing studies from several model systems have suggested that diverse and abundant small RNAs may be derived from tRNA, but the function of these molecules remains undefined. Here, we demonstrate that one such tRNA-derived fragment, cloned from human mature B cells and designated CU1276, in fact possesses the functional characteristics of a microRNA, including a DICER1-dependent biogenesis, physical association with Argonaute proteins, and the ability to repress mRNA transcripts in a sequence-specific manner. Expression of CU1276 is abundant in normal germinal center B cells but absent in germinal center-derived lymphomas, suggesting a role in the pathogenesis of this disease.

Identification of the human mature B cell miRNome.

The full set of microRNAs (miRNAs) in the human genome is not known. Because presently known miRNAs have been identified by virtue of their abundant expression in a few cell types, many tissue-specific miRNAs remain unrevealed. To understand the role of miRNAs in B cell function and lymphomagenesis, we generated short-RNA libraries from normal human B cells at different stages of development (naive, germinal center, memory) and from a Burkitt lymphoma cell line.