Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.
We demonstrate that CD27 co-stimulation increases the number of Tregs and limits lesion development and inflammation in experimental atherosclerosis, particularly during early stages of disease. Thus, our study suggests that promotion of CD27 function may mitigate atherosclerosis.
A better understanding of the molecular mechanisms of platelet-related immune activity allows their utilization as powerful diagnostic tools or targets of therapeutic intervention. Those findings might help to develop new classes of drugs which may supplement or replace classical anticoagulants and help clinicians to tackle CVD more efficiently.
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Introduction and background
Through recent advances in cancer care, the number of long-term survivors has continuously increased. As a result, repetitive use of local radiotherapy for curative or palliative indications might have increased as well. This analysis aims to describe patterns of care and outcome of patients treated with multiple courses of repeat radiotherapy.
Materials and methods
All patients treated with radiotherapy between 2011 and 2019 at our department of Radiation Oncology were included into this analysis. A course of radiotherapy was defined as all treatment sessions to one anatomical site under one medical indication. Demographics, cancer and treatment characteristics and overall survival of patients having undergone multiple radiotherapy courses (minimum n = 5) were evaluated.
Results
The proportion of cancer patients treated with a minimum five courses of radiotherapy increased continuously from 0.9% in 2011 to 6.5% in 2019. In the 112 patients treated with a minimum of five radiotherapy courses, the primary tumor was lung in 41.9% (n = 47), malignant melanoma in 8.9% (n = 10) and breast in 8.0% (n = 9) of cases. A median interval of 3 years (maximum 8 years) elapsed between the first and the last radiotherapy course. The maximum number of courses in a single patient were n = 10. Treatment intent was curative or palliative in 46.4% and 53.6% for the first radiotherapy, respectively. The proportion of curative intent decreased to 11.6% at the 5th, and the last radiotherapy course was following a palliative intent in all patients. Five-year overall survival measured from the 1st radiotherapy course was 32.7%. Median overall survival was 3.3, 2.4, 1.3, and 0.6 years when measured from the 1st, the 1st palliative, the 5th and last course of radiotherapy, respectively.
Discussion and conclusion
A continuously increasing number of patients is treated with multiple courses of radiotherapy throughout their long-term cancer survivorship.
The co-stimulatory molecule CD70 is expressed on activated immune cells and is known to modulate responses of T, B, and NK cells via its receptor CD27. Until now, there is only limited data describing the role of CD70 in atherosclerosis. We observed that ruptured human carotid atherosclerotic plaques displayed higher CD70 expression than stable carotid atherosclerotic plaques, and that CD70 expression in murine atheroma localized to macrophages. Lack of CD70 impaired the inflammatory capacity (e. g. reactive oxygen species and nitric oxide production) of bone marrow-derived macrophages, increased both M1-like and M2-like macrophage markers, and rendered macrophages metabolically inactive and prone to apoptosis. Moreover, CD70-deficient macrophages expressed diminished levels of scavenger receptors and ABC-transporters, impairing uptake of oxidised low-density lipoprotein (oxLDL) and cholesterol efflux, respectively. Hyperlipidaemic Apoe mice reconstituted with CD70-deficient bone marrow displayed a profound increase in necrotic core size, plaque area, and number of lesional macrophages as compared to mice receiving control bone marrow. Accordingly, 18 week-old, chow diet-fed CD70-deficient Apoe mice displayed larger atheroma characterised by lower cellularity and more advanced plaque phenotype than Apoe mice. In conclusion, CD70 promotes macrophage function and viability and is crucial for effective phagocytosis and efflux of oxLDL. Deficiency in CD70 results in more advanced atheroma. Our data suggest that CD70 mitigates atherosclerosis at least in part by modulating macrophage function.
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