Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion

Prevalence of Abdominal Aortic Aneurysms in the General Population and in Subgroups at High Cardiovascular Risk in Italy. Results of the RoCAV Population Based Study

Objectives: Prevalence data on abdominal aortic aneurysm (AAA) in women, subjects younger than 65 years and in subgroups carrying specific risk factors are scarce. AAA prevalence was evaluated in an Italian population including women and younger subjects, stratifying for the presence of cardiovascular disease (CVD) risk factors and CVD risk score. Materials and methods: A population based cross-sectional study was conducted between 2013 and 2016. Men aged 50-75 and women aged 60-75 years, resident in the city of Varese (northern Italy), were randomly selected from the civil registry. A vascular surgeon performed an abdominal aortic ultrasound scan at four sites using the leading edge to leading edge method. CVD risk score was computed using the ESC-SCORE algorithm. The age and gender specific prevalence was estimated, stratifying by the presence of CVD and cardiovascular risk factors. Results: Among the 3755 subjects with a valid ultrasound measurement, 63 subjects with an AAA were identified (5 referred for surgical intervention), among whom 34 were not previously known (30 men 1.3%, 95% CI 0.9-1.8; 4 women 0.3%, 95% CI 0.1-0.8). Considering age classes in men only, the highest prevalence of screen detected AAA was found in subjects aged 65-70 (1.2%; 95% CI 0.4-2.5) and 70-75 (2.5%; 95% CI 1.4-4.0) years. Among 65-75 year old men, the highest AAA prevalence was found in subjects with a previous myocardial infarction (MI 4.9%, 95% CI 2.0-9.9) and in ever-smokers reporting more than 15 pack years of smoking (4.1%, 95% CI 2.5-6.3). Among the younger subjects, those having an ESC-SCORE higher than 5% or a previous CVD (MI or stroke) showed a prevalence of 1.4% (95% CI 0.3-4.2; prevalence including subaneurysms 6.7%, 95% CI 3.7-11.0%). Conclusions: In the study population, both a general screening program in 65-75 year old men and an approach targeted to subgroups at higher risk merit evaluation in a cost-effectiveness study. In 50-64 year old men, strategies for population selection should consider CVD risk stratification tools