Multiparametric cellular and spatial organization in cancer tissue lesions with a streamlined pipeline.

Multiplex immunostaining analysis remains fragmented, underperforming and labour intensive despite tissue proteomic methodologies achieving ever-increasing marker complexity. Here we propose an open-source, user-guided automated pipeline that streamlines start-to-finish, single-cell resolution analysis of whole-slide tissue, named multiplex-imaging analysis, registration, quantification and overlaying (MARQO). MARQO integrates elastic image registration, iterative nuclear segmentation, unsupervised clustering with mini-batch k-means and user-guided cell classification through a graphical interface.

An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

Myeloid cells are known to suppress antitumour immunity. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype.

Intratumoral dendritic cell-CD4 T helper cell niches enable CD8 T cell differentiation following PD-1 blockade in hepatocellular carcinoma.

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13CH25HIL-21PD-1CD4 T helper cells ("CXCL13 T") and Granzyme K PD-1 effector-like CD8 T cells, whereas terminally exhausted CD39TOXPD-1CD8 T cells dominated in nonresponders.

A shift in lung macrophage composition is associated with COVID-19 severity and recovery.

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression.

Utilising low-cost, easy-to-use microscopy techniques for early peritonitis infection screening in peritoneal dialysis patients.

Peritoneal dialysis (PD) patients are at high risk for peritonitis, an infection of the peritoneum that affects 13% of PD users annually. Relying on subjective peritonitis symptoms results in delayed treatment, leading to high hospitalisation costs, peritoneal scarring, and premature transition to haemodialysis. We have developed and tested a low-cost, easy-to-use technology that uses microscopy and image analysis to screen for peritonitis across the effluent drain tube.

Spatial CRISPR genomics identifies regulators of the tumor microenvironment.

While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition.

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer.

Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells , cell-line and patient-derived xenografts , and prostate cancer patient specimens.

The interaction of CD4 helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response.

Despite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4PD-1CXCL13 T cells are a major interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells.

Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.

Background: Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma.

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression.

Plectin is a regulator of prostate cancer growth and metastasis.

Prostate cancer is responsible for over 30,000 US deaths annually, attributed largely to incurable metastatic disease. Here, we demonstrate that high levels of plectin are associated with localized and metastatic human prostate cancer when compared to benign prostate tissues. Knock-down of plectin inhibits prostate cancer cell growth and colony formation in vitro, and growth of prostate cancer xenografts in vivo.