Hematopoietic PI3Kδ deficiency aggravates murine atherosclerosis through impairment of regulatory T cells.

Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B-cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr-/- mice resulted in hindered T- and B-cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels. However, despite markedly impaired peripheral proinflammatory Th1 cells and atheromatous CD4+ T cells, the unexpected net effect of hematopoietic PI3Kδ deficiency was aggravated vascular inflammation and atherosclerosis. Further analyses revealed that PI3Kδ deficiency impaired numbers, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs), whereas macrophage biology remained largely unaffected. Adoptive transfer of wild-type Tregs fully restrained the atherosclerotic plaque burden in Ldlr-/- mice lacking hematopoietic PI3Kδ, whereas PI3Kδ deficient Tregs failed to mitigate disease. Numbers of atheroprotective B-1 and proatherogenic B-2 cells as well serum immunoglobulin levels remained unaffected by adoptively transferred wild-type Tregs. In conclusion, we demonstrate that hematopoietic PI3Kδ ablation promotes atherosclerosis. Mechanistically, we identified PI3Kδ signaling as a powerful driver of atheroprotective Treg responses, which outweigh PI3Kδ driven proatherogenic effects of adaptive immune cells like Th1 cells.

Cancer Development and Progression in Patients with Heart Failure.

PURPOSE OF REVIEW: The co-occurrence of heart failure (HF) and cancer represents a complex and multifaceted medical challenge. Patients with prevalent cardiovascular disease (CVD), particularly HF, exhibit an increased risk of cancer development, raising questions about the intricate interplay between these two prevalent conditions. This review aims to explore the evolving landscape of cancer development in patients with HF, shedding light on potential mechanisms, risk factors, and clinical implications. RECENT FINDINGS: Epidemiological data suggests higher cancer incidences and higher cancer mortality in HF patients, which are potentially more common in patients with HF with preserved ejection fraction due to related comorbidities. Moreover, recent preclinical data identified novel pathways and mediators including the protein SerpinA3 as potential drivers of cancer progression in HF patients, suggesting HF as an individual risk factor for cancer development. The review emphasizes preliminary evidence supporting cancer development in patients with HF, which offers several important clinical interventions such as cancer screening in HF patients, prevention addressing both HF and cancer, and molecular targets to treat cancer. However, there is need for more detailed understanding of molecular and cellular cross-talk between cancer and HF which can be derived from prospective assessments of cancer-related outcomes in CV trials and preclinical research of molecular mechanisms.

Macrophage mediators and mechanisms in cardiovascular disease.

Macrophages are major players in myocardial infarction (MI) and atherosclerosis, two major cardiovascular diseases (CVD). Atherosclerosis is caused by the buildup of cholesterol-rich lipoproteins in blood vessels, causing inflammation, vascular injury, and plaque formation. Plaque rupture or erosion can cause thrombus formation resulting in inadequate blood flow to the heart muscle and MI. Inflammation, particularly driven by macrophages, plays a central role in both atherosclerosis and MI. Recent integrative approaches of single-cell analysis-based classifications in both murine and human atherosclerosis as well as experimental MI showed overlap in origin, diversity, and function of macrophages in the aorta and the heart. We here discuss differences and communalities between macrophages in the heart and aorta at steady state and in atherosclerosis or upon MI. We focus on markers, mediators, and functional states of macrophage subpopulations. Recent trials testing anti-inflammatory agents show a major benefit in reducing the inflammatory burden of CVD patients, but highlight a necessity for a broader understanding of immune cell ontogeny and heterogeneity in CVD. The novel insights into macrophage biology in CVD represent exciting opportunities for the development of novel treatment strategies against CVD.

IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC. DESIGN: Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models. RESULTS: Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo. CONCLUSIONS: We identified Tc17 as a novel protumourigenic CD8+ T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.

Immunotherapeutic Strategies in Cancer and Atherosclerosis-Two Sides of the Same Coin.

The development and clinical approval of immunotherapies has revolutionized cancer therapy. Although the role of adaptive immunity in atherogenesis is now well-established and several immunomodulatory strategies have proven beneficial in preclinical studies, anti-atherosclerotic immunotherapies available for clinical application are not available. Considering that adaptive immune responses are critically involved in both carcinogenesis and atherogenesis, immunotherapeutic approaches for the treatment of cancer and atherosclerosis may exert undesirable but also desirable side effects on the other condition, respectively. For example, the high antineoplastic efficacy of immune checkpoint inhibitors, which enhance effector immune responses against tumor cells by blocking co-inhibitory molecules, was recently shown to be constrained by substantial proatherogenic properties. In this review, we outline the specific role of immune responses in the development of cancer and atherosclerosis. Furthermore, we delineate how current cancer immunotherapies affect atherogenesis and discuss whether anti-atherosclerotic immunotherapies may similarly have an impact on carcinogenesis.