The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype.

Tumor-associated macrophages (TAMs) are innate immune cells that exert far reaching influence over the tumor microenvironment (TME). Depending on cues within the local environment, TAMs may promote tumor angiogenesis, cancer cell invasion and immunosuppression, or, alternatively, inhibit tumor progression via neoantigen presentation, tumoricidal reactive oxygen species generation and pro-inflammatory cytokine secretion. Therefore, TAMs have a pivotal role in determining tumor progression and response to therapy.

Functional links between the microbiome and the molecular pathways of colorectal carcinogenesis.

Colorectal cancer (CRC) is a common cancer, with a concerning rise in early-onset CRC cases, signalling a shift in disease epidemiology. Whilst our understanding of the molecular underpinnings of CRC has expanded, the complexities underlying its initiation remain elusive, with emerging evidence implicating the microbiome in CRC pathogenesis. This review synthesizes current knowledge on the intricate interplay between the microbiome, tumour microenvironment (TME), and molecular pathways driving CRC carcinogenesis.

Detection of Chitinase 3-Like 1 in Symptomatic Primary Care Patient Faecal Samples is Not a Reliable Biomarker of Colonic Lesions.

Background: The current gold standard non-invasive test for detecting pre-cancerous changes is the faecal immunochemical test (FIT). However, this test can lack sensitivity and specificity and testing for another biomarker may address these limitations. Chitinase 3-like 1 (CHI3L1) is emerging as a potential biomarker of inflammation-associated carcinogenic changes in epithelial cells.

CD36 down regulation by the macrophage antioxidant 7,8-dihydroneopterin through modulation of PPAR-γ activity.

CD36 is the key scavenger receptor driving the formation of cholesterol-loaded foam cells, the principal cellular component of atherosclerotic plaques. CD36 is down regulated by 7,8-dihydroneopterin, a potent superoxide and hypochlorite scavenging antioxidant generated by interferon-γ stimulated macrophages. 7,8-dihydroneopterin downregulates CD36 mRNA and protein levels so inhibiting macrophage foam cell formation .

Effect of immune modulation on the skeletal muscle mitochondrial exercise response: An exploratory study in mice with cancer.

Cancer causes mitochondrial alterations in skeletal muscle, which may progress to muscle wasting and, ultimately, to cancer cachexia. Understanding how exercise adaptations are altered by cancer and cancer treatment is important for the effective design of exercise interventions aimed at improving cancer outcomes. We conducted an exploratory study to investigate how tumor burden and cancer immunotherapy treatment (anti-PD-1) modify the skeletal muscle mitochondrial response to exercise training in mice with transplantable tumors (B16-F10 melanoma and EO771 breast cancer).

Effects of exercise and anti-PD-1 on the tumour microenvironment.

Immune checkpoint inhibition is highly effective in treating a subset of patients with certain cancers, such as malignant melanoma. However, a large proportion of patients will experience treatment resistance, and other tumour types, such as breast cancer, have thus far proven largely refractory to immune checkpoint inhibitors as single agents. Exercise has been associated with improved cancer patient survival, has known immune-modulatory effects, may improve anti-tumour immunity and may normalise tumour blood vessels.

Functional effects of immune complexes formed between pembrolizumab and patient-generated anti-drug antibodies.

The PD-1-targeting IgG antibody pembrolizumab has significant anti-tumor activity in a proportion of stage IV melanoma patients. A subset of patients develop anti-drug antibodies (ADA) which can form immune complexes (IC) with pembrolizumab. Although IC can induce powerful, Fc-mediated, immune-regulatory effects, their functional impact during pembrolizumab treatment is unclear.

Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice.

Preclinical studies have shown a larger inhibition of tumour growth when exercise begins prior to tumour implant (preventative setting) than when training begins after tumour implant (therapeutic setting). However, post-implantation exercise may alter the tumour microenvironment to make it more vulnerable to treatment by increasing tumour perfusion while reducing hypoxia. This has been shown most convincingly in breast and prostate cancer models to date and it is unclear whether other tumour types respond in a similar way.

Neopterin formation through radical scavenging of superoxide by the macrophage synthesised antioxidant 7,8-dihydroneopterin.

Clinical measurement of neopterin has been extensively used as a marker of inflammation but the in vivo mechanism generating neopterin is poorly understood. Neopterin is described as the oxidation product of 7,8-dihydroneopterin, a potent antioxidant generated by monocyte/macrophages in response to interferon-γ. While peroxyl and hydroxyl scavenging generates dihydroxanthopterin, hypochlorite efficiently oxidises 7,8-dihydroneopterin into neopterin, but this reaction alone does not explain the high levels of neopterin seen in clinical data.

Development of a competitive binding homogeneous mobility shift assay for the quantification of adalimumab levels in patient serum.

Adalimumab is a TNF specific monoclonal widely used therapeutically. Monitoring adalimumab levels is important for guiding treatment strategies and is predominantly performed using an ELISA. The homogeneous mobility shift assay (HMSA) has many advantages over an ELISA for adalimumab monitoring but current HMSA methodologies do not discriminate between adalimumab and other TNF specific monoclonals such as infliximab.

Discrimination of Anti-drug Antibodies With Neutralizing Capacity in Infliximab- and Adalimumab-Treated Patients: Comparison of the Homogeneous Mobility Shift Assay and the Affinity Capture and Elution Assay.

Background: The measurement of anti-drug antibody (ADA) levels in adalimumab (ADAL)-treated and infliximab (IFX)-treated patients is critical for guiding therapeutic strategies. The homogeneous mobility shift assay (HMSA) and affinity capture elution (ACE) assay provide effective, drug-tolerant formats for measuring total ADA levels. However, their ability to discriminate between ADA from samples with or without neutralizing capacity is unclear and therefore was analyzed in this study.

Impact of increased access to novel agents on the survival of multiple myeloma patients treated at a single New Zealand centre.

Background: The impact of changes in novel agent (NA) usage on the survival of multiple myeloma (MM) patients in real-world hospital settings is unclear. In New Zealand (NZ) in 2011, frontline bortezomib became available and thalidomide availability was expanded.

Aim: This retrospective study analyses the impact these change had on the survival of MM patients treated at a NZ hospital.

Infliximab and adalimumab concentrations and anti-drug antibodies in inflammatory bowel disease control using New Zealand assays.

Background: Therapeutic drug monitoring of anti-tumour necrosis factor (TNF) drugs and anti-drug antibodies (ADA) is now recommended in the treatment of inflammatory bowel disease. However, assay types and drug concentration thresholds are still debated.

Aim: To correlate inflammatory bowel disease activity in a New Zealand cohort with trough concentrations of infliximab and adalimumab, and ADA using locally developed competitive-binding enzyme-linked immunosorbent assays (ELISA) to establish threshold concentrations.

Induced macrophage activation in live excised atherosclerotic plaque.

Atherosclerotic plaques are complex tissues containing many different cell types. Macrophages contribute to inflammation, formation of the necrotic core, and plaque rupture. We examined whether macrophages in plaque can be activated and compared this to monolayer cells.

Helicobacter pylori outer membrane vesicles inhibit human T cell responses via induction of monocyte COX-2 expression.

The modulation of T cell responses by Helicobacter pylori is thought to potentiate both H. pylori persistence and development of gastric pathologies including cancer. Release of outer membrane vesicles (OMV) by H.

Effect of 7,8-dihydroneopterin mediated CD36 down regulation and oxidant scavenging on oxidised low-density lipoprotein induced cell death in human macrophages.

The role of CD36 in oxidised low-density lipoprotein (oxLDL) mediated cell death was examined by down regulating the receptor level with the macrophage generated antioxidant 7,8-dihydroneopterin. Down regulation of CD36 protein levels in human monocyte derived macrophages by 7,8-dihydroneopterin corresponded to a decrease in CD36-mRNA. The oxidation products of 7,8-dihydroneopterin, dihydroxanthopterin and neopterin did not significantly down regulate CD36.

Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified.

Cutaneous squamous cell carcinomas with markers of increased metastatic risk are associated with elevated numbers of neutrophils and/or granulocytic myeloid derived suppressor cells.

Background: A subset of presenting cutaneous squamous cell carcinomas (CSCC) is high risk with respect to their high rates of recurrence, metastasis and patient death. The identification of such high risk CSCC is problematic. Neutrophil and granulocytic myeloid derived suppressor cell (G-MDSC) numbers are elevated in a number of cancers, but their association with current markers of high risk tumors in the setting of CSCC is unknown.