Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool.

Comparative toxicological assessment of cigarettes and new category products via an multiplex proteomics platform.

Cigarette smoking is a risk factor for several diseases such as cancer, cardiovascular disease (CVD), and chronic obstructive pulmonary diseases (COPD), however, the underlying mechanisms are not fully understood. Alternative nicotine products with reduced risk potential (RRPs) including tobacco heating products (THPs), and e-cigarettes have recently emerged as viable alternatives to cigarettes that may contribute to the overall strategy of tobacco harm reduction due to the significantly lower levels of toxicants in these products' emissions as compared to cigarette smoke. Assessing the effects of RRPs on biological responses is important to demonstrate the potential value of RRPs towards tobacco harm reduction.

The Clinical Relevance of the Infiltrating Immune Cell Composition in Kidney Transplant Rejection.

Key Points: The estimated composition of immune cells in kidney transplants correlates poorly with the primary rejection categories defined by Banff criteria. Spatial cell distribution could be coupled with a detailed cellular composition to assess causal triggers for allorecognition. Intragraft CD8temra cells showed strong and consistent association with graft failure, regardless of the Banff rejection phenotypes.

Recent advancements in tumour microenvironment landscaping for target selection and response prediction in immune checkpoint therapies achieved through spatial protein multiplexing analysis.

Immune checkpoint therapies have significantly advanced cancer treatment. Nevertheless, the high costs and potential adverse effects associated with these therapies highlight the need for better predictive biomarkers to identify patients who are most likely to benefit from treatment. Unfortunately, the existing biomarkers are insufficient to identify such patients.

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection.

Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue.

Single-cell molecular profiling using ex vivo functional readouts fuels precision oncology in glioblastoma.

Background: Functional profiling of freshly isolated glioblastoma (GBM) cells is being evaluated as a next-generation method for precision oncology. While promising, its success largely depends on the method to evaluate treatment activity which requires sufficient resolution and specificity.

Methods: Here, we describe the 'precision oncology by single-cell profiling using ex vivo readouts of functionality' (PROSPERO) assay to evaluate the intrinsic susceptibility of high-grade brain tumor cells to respond to therapy.

Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma.

Background: Loss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy.

Next-Generation Pathology Using Multiplexed Immunohistochemistry: Mapping Tissue Architecture at Single-Cell Level.

Single-cell omics aim at charting the different types and properties of all cells in the human body in health and disease. Over the past years, myriads of cellular phenotypes have been defined by methods that mostly required cells to be dissociated and removed from their original microenvironment, thus destroying valuable information about their location and interactions. Growing insights, however, are showing that such information is crucial to understand complex disease states.

ELIMINATOR: essentiality analysis using multisystem networks and integer programming.

A gene is considered as essential when it is indispensable for cells to grow and replicate in a certain environment. However, gene essentiality is not a structural property but rather a contextual one, which depends on the specific biological conditions affecting the cell. This circumstantial essentiality of genes is what brings the attention of scientist since we can identify genes essential for cancer cells but not essential for healthy cells.

Mapping the Immune Landscape in Metastatic Melanoma Reveals Localized Cell-Cell Interactions That Predict Immunotherapy Response.

Unlabelled: While immune checkpoint-based immunotherapy (ICI) shows promising clinical results in patients with cancer, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and nonmalignant cells. Although insights into the mechanisms that modulate the pivotal antitumoral activity of cytotoxic T cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types.

Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy.

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course.

A fully defined matrix to support a pluripotent stem cell derived multi-cell-liver steatohepatitis and fibrosis model.

Chronic liver injury, as observed in non-alcoholic steatohepatitis (NASH), progressive fibrosis, and cirrhosis, remains poorly treatable. Steatohepatitis causes hepatocyte loss in part by a direct lipotoxic insult, which is amplified by derangements in the non-parenchymal cellular (NPC) interactive network wherein hepatocytes reside, including, hepatic stellate cells, liver sinusoidal endothelial cells and liver macrophages. To create an in vitro culture model encompassing all these cells, that allows studying liver steatosis, inflammation and fibrosis caused by NASH, we here developed a fully defined hydrogel microenvironment, termed hepatocyte maturation (HepMat) gel, that supports maturation and maintenance of pluripotent stem cell (PSC) derived hepatocyte- and NPC-like cells for at least one month.

Blood Immunosenescence Signatures Reflecting Age, Frailty and Tumor Immune Infiltrate in Patients with Early Luminal Breast Cancer.

Background: Immune/senescence-related host factors play a pivotal role in numerous biological and pathological process like aging, frailty and cancer. The assessment of these host factors via robust, non-invasive, and easy-to-measure blood biomarkers could improve insights in these processes. Here, we investigated in a series of breast cancer patients in which way single circulating biomarkers or biomarker panels relate to chronological age, frailty status, and tumor-associated inflammatory microenvironment.

Multiplexed Immunohistochemistry and Digital Pathology as the Foundation for Next-Generation Pathology in Melanoma: Methodological Comparison and Future Clinical Applications.

The state-of-the-art for melanoma treatment has recently witnessed an enormous revolution, evolving from a chemotherapeutic, "one-drug-for-all" approach, to a tailored molecular- and immunological-based approach with the potential to make personalized therapy a reality. Nevertheless, methods still have to improve a lot before these can reliably characterize all the tumoral features that make each patient unique. While the clinical introduction of next-generation sequencing has made it possible to match mutational profiles to specific targeted therapies, improving response rates to immunotherapy will similarly require a deep understanding of the immune microenvironment and the specific contribution of each component in a patient-specific way.

A Multi-Omics Analysis of Metastatic Melanoma Identifies a Germinal Center-Like Tumor Microenvironment in HLA-DR-Positive Tumor Areas.

The emergence of immune checkpoint inhibitors has dramatically changed the therapeutic landscape for patients with advanced melanoma. However, relatively low response rates and a high incidence of severe immune-related adverse events have prompted the search for predictive biomarkers. A positive predictive value has been attributed to the aberrant expression of Human Leukocyte Antigen-DR (HLA-DR) by melanoma cells, but it remains unknown why this is the case.

Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization.

Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly understood. Here, we employed single-cell RNA sequencing and CITE-seq to map the glioblastoma immune landscape in mouse tumors and in patients with newly diagnosed disease or recurrence.

SOX10 is as specific as S100 protein in detecting metastases of melanoma in lymph nodes and is recommended for sentinel lymph node assessment.

Background: Sentinel lymph node (SLN) biopsy remains crucial for melanoma staging. The European Organisation for Research and Treatment of Cancer Melanoma Group recommends performing immunohistochemical stainings for reproducible identification of melanoma metastases. S100 protein (pS100) is a commonly used melanocytic antigen because of its high sensitivity in spite of relatively low specificity.

A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling.

The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies.