Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control.

Background: The immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated immune tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with reprogramming strategies focusing on inhibitors of phosphoinositide 3-kinase-gamma (PI3Kγ) due to restricted immune cell expression. Inhibition of PI3Kγ alone is ineffective in PDAC, despite increased infiltration of CD8+ T cells.

Tissue-resident natural killer cells support survival in pancreatic cancer through promotion of cDC1-CD8 T activity.

The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T-cell activity) have had limited success.

Using Spectral Flow Cytometry to Characterize Anti-Tumor Immunity in Orthotopic and Subcutaneous Mouse Models of Cancer.

Mouse models remain at the forefront of immuno-oncology research, providing invaluable insights into the complex interactions between the immune system and developing tumors. While several flow cytometry panels have been developed to study cancer immunity in mice, most are limited in their capacity to address the complexity of anti-cancer immune responses. For example, many of the panels developed to date focus on a restricted number of leukocyte populations (T cells or antigen-presenting cells), failing to include the multitude of other subsets that participate in anti-cancer immunity.

Targeting PI3K-gamma in myeloid driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature.

The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences tumour progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), contribute to immune suppression in the TME (Nakamura and Smyth in Cell Mol Immunol 17(1):1-12 (2020). https://doi.

Targeted irradiation in an autochthonous mouse model of pancreatic cancer.

The value of radiotherapy in the treatment of pancreatic cancer has been the subject of much debate but limited preclinical research. We hypothesise that the poor translation of radiation research into clinical trials of radiotherapy in pancreatic cancer is due, in part, to inadequate preclinical study models. Here, we developed and refined methods for targeted irradiation in autochthonous mouse models of pancreatic cancer, using a small animal radiotherapy research platform.

Effectiveness of building-level sewage surveillance during both community-spread and sporadic-infection phases of SARS-CoV-2 in a university campus population.

Pathogen surveillance within wastewater rapidly progressed during the SARS-CoV-2 pandemic and informed public health management. In addition to the successful monitoring of entire sewer catchment basins at the treatment facility scale, subcatchment or building-level monitoring enabled targeted support of resource deployment. However, optimizing the temporal and spatial resolution of these monitoring programs remains complex due to population dynamics and within-sewer physical, chemical, and biological processes.

Immune checkpoint inhibition: a future guided by radiology.

The limitation of the function of antitumour immune cells is a common hallmark of cancers that enables their survival. As such, the potential of immune checkpoint inhibition (ICI) acts as a paradigm shift in the treatment of a range of cancers but has not yet been fully capitalised. Combining minimally and non-invasive locoregional therapies offered by radiologists with ICI is now an active field of research with the aim of furthering therapeutic capabilities in medical oncology.

Ionizing Radiation Drives Key Regulators of Antigen Presentation and a Global Expansion of the Immunopeptidome.

Little is known about the pathways regulating MHC antigen presentation and the identity of treatment-specific T cell antigens induced by ionizing radiation. For this reason, we investigated the radiation-specific changes in the colorectal tumor cell proteome. We found an increase in DDX58 and ZBP1 protein expression, two nucleic acid sensing molecules likely involved in induction of the dominant interferon response signature observed after genotoxic insult.

FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy.

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2) regress dependent on T cells.

Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model.

Background: Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy with radiotherapy fractions used to treat prostate cancer. We investigated tumour immune microenvironment responses of pre-clinical prostate cancer models to radiotherapy.

The unique immune microenvironment of liver metastases: Challenges and opportunities.

Liver metastases from gastrointestinal and non-gastrointestinal malignancies remain a major cause of cancer-related mortality and a major clinical challenge. The liver has unique properties that facilitate metastatic expansion, including a complex immune system that evolved to dampen immunity to neoantigens entering the liver from the gut, through the portal circulation. In this review, we describe the unique microenvironment encountered by cancer cells in the liver, focusing on elements of the innate and adaptive immune response that can act as a double-edge sword, contributing to the elimination of cancer cells on the one hand and promoting their survival and growth, on the other.

Inter-operator variability in pPOSSUM scores: a note of caution.

Purpose: Predicting perioperative morbidity and mortality can be achieved by several risk predicting algorithms. In the UK, the National Emergency Laparotomy Audit, mandated for all patients undergoing emergency laparotomy, uses pPOSSUM as its risk prediction tool. However, there is no literature reporting the inter-operator variability in calculating the score.

Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition.

Hepatic metastatic growth is dependent upon stromal factors including the matrisomal proteins that make up the extracellular matrix (ECM). Laminins are ECM glycoproteins with several functions relevant to tumour progression including angiogenesis. We investigated whether metastatic colon cancer cells produce the laminins required for vascular basement membrane assembly as a mechanism for the promotion of angiogenesis and liver metastasis growth.

Improving Colorectal Cancer Screening Rates in Patients Referred to a Gastroenterology Clinic.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. Colonoscopy and fecal immunochemistry testing (FIT) are the primary recommended CRC screening modalities. The purpose of this study is to improve rates of CRC screening in Veterans and County hospital patients referred to gastroenterology fellow's clinics.

Racial Disparities in Liver Transplantation for Hepatocellular Carcinoma Are Not Explained by Differences in Comorbidities, Liver Disease Severity, or Tumor Burden.

Black patients have higher mortality and are less likely to receive liver transplantation for hepatocellular carcinoma (HCC) than white patients. Reasons for these disparities have not been fully elucidated. Comorbid disease, liver disease severity, cirrhosis etiologies, and tumor characteristics were compared between black and white patients with HCC seen at the Indiana University Academic Medical Center from January 2000 to June 2014.

Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis.

Background: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood.

Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design.

Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade.

Emerging evidence suggests a role for radiation in eliciting anti-tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony-stimulating factor 1 (CSF-1).

Lower expression of tumor microRNA-26a is associated with higher recurrence in patients with hepatocellular carcinoma undergoing surgical treatment.

Background And Objectives: Hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) exhibit lower tumor microRNA-26a (miR-26a) expression which is associated with worse outcomes. It is unknown if similar miR-26a loss occurs in HCC developed in other liver diseases. We examined tumor miR-26a expression and its impact on recurrence and mortality in a North American HCC cohort.

Gemcitabine-Induced TIMP1 Attenuates Therapy Response and Promotes Tumor Growth and Liver Metastasis in Pancreatic Cancer.

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC.

A meta-analysis of CXCL12 expression for cancer prognosis.

Background: CXCL12 (SDF1) is reported to promote cancer progression in several preclinical models and this is corroborated by the analysis of human tissue specimens. However, the relationship between CXCL12 expression and cancer survival has not been systematically assessed.

Methods: We conducted a systematic review and meta-analysis of studies that evaluated the association between CXCL12 expression and cancer survival.

Radiologically Determined Sarcopenia Predicts Morbidity and Mortality Following Abdominal Surgery: A Systematic Review and Meta-Analysis.

Background: Individualised risk prediction is crucial if targeted pre-operative risk reduction strategies are to be deployed effectively. Radiologically determined sarcopenia has been shown to predict outcomes across a range of intra-abdominal pathologies. Access to pre-operative cross-sectional imaging has resulted in a number of studies investigating the predictive value of radiologically assessed sarcopenia over recent years.

Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice.

Unlabelled: Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils.

PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner.

The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.

Unlabelled: Biliary atresia (BA) is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease.