Implications of metabolism-driven myeloid dysfunctions in cancer therapy

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy

Differences in the vascular and metabolic profiles between metabolically healthy and unhealthy obesity

Abstract Individuals suffering from severe obesity but not presenting the typical metabolic alterations, are included in a subclass of obesity defined Metabolically Healthy Obesity (MHO). The physiological factors underlying what seems a protective and favourable metabolic profile remain unclear. MHO individuals are more insulin-sensitive, have relatively lower visceral/ectopic fat accumulation and reduced levels of chronic low-grade inflammation, compared to obese subjects with co-morbidities. The study of MHO subjects represents a great opportunity for the recognition of the mechanisms that lead to the vascular and metabolic complications in obesity. Finding the differences among the metabolic profile of visceral adipose tissue between metabolically healthy and unhealthy obesity may lead to future personalized and stratified therapies.This review article summarizes the pathomechanisms and metabolic changes in MHO and metabolically unhealthy obesity (MUO), reviews clinical studies on the subject, and discusses preventive and therapeutic options

A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient

: Triple-negative breast cancer (TNBC) is the most aggressive subtype of mammary carcinoma. Here, we describe a case of an 81-year-old female diagnosed with ductal triple negative breast cancer with a germline pathogenic variant in BReast CAncer gene2 (BRCA2). Genetic testing also revealed the presence of four somatic mutations in the ephrin type-A receptor 3 (EphA3), TP53, BRCA1-associated protein (BAP1), and MYB genes. The BRCA2, TP53, and BAP1 gene mutations are highly predictive of a defective homologous recombination repair system and subsequent chromosomal instability in this patient. Coherently, the patient displayed a strong homologous recombination deficiency signature and high tumor mutational burden status, which are generally associated with increased probability of immune neoantigens formation and presentation, and with tumor immunogenicity. Analysis of immune checkpoint revealed high expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), programmed death 1 (PD1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), suggesting that the patient might likely benefit from immunotherapies. Altogether, these findings support an unveiled link between BRCA2 inactivation, HR deficiency and increased expression of immune checkpoints in TNBC. This clinical case highlights the importance of screening TNBC patients for genetic mutations and TMB biomarkers in order to predict the potential efficacy of immunotherapy

Protective Effects of Recombinant Human Angiogenin in Keratinocytes: New Insights on Oxidative Stress Response Mediated by RNases

Human angiogenin (ANG) is a 14-kDa ribonuclease involved in different pathophysiological processes including tumorigenesis, neuroprotection, inflammation, innate immunity, reproduction, the regeneration of damaged tissues and stress cell response, depending on its intracellular localization. Under physiological conditions, ANG moves to the cell nucleus where it enhances rRNA transcription; conversely, recent reports indicate that under stress conditions, ANG accumulates in the cytoplasmic compartment and modulates the production of tiRNAs, a novel class of small RNAs that contribute to the translational inhibition and recruitment of stress granules (SGs). To date, there is still limited and controversial experimental evidence relating to a hypothetical role of ANG in the epidermis, the outermost layer of human skin, which is continually exposed to external stressors. The present study collects compelling evidence that endogenous ANG is able to modify its subcellular localization on HaCaT cells, depending on different cellular stresses. Furthermore, the use of recombinant ANG allowed to determine as this special enzyme is effectively able to counter at various levels the alterations of cellular homeostasis in HaCaT cells, actually opening a new vision on the possible functions that this special enzyme can support also in the stress response of human skin

Aged mesenchymal stem cells and inflammation: from pathology to potential therapeutic strategies

Natural ageing of organisms and corresponding age-related diseases result mainly from stem cell ageing and "inflammaging". Mesenchymal stem cells (MSCs) exhibit very high immune-regulating capacity and are promising candidates for immune-related disease treatment. However, the effect of MSC application is not satisfactory for some patients, especially in elderly individuals. With ageing, MSCs undergo many changes, including altered cell population reduction and differentiation ability, reduced migratory and homing capacity and, most important, defective immunosuppression. It is necessary to explore the relationship between the "inflammaging" and aged MSCs to prevent age-related diseases and increase the therapeutic effects of MSCs. In this review, we discuss changes in naturally ageing MSCs mainly from an inflammation perspective and propose some ideas for rejuvenating aged MSCs in future treatments

Immunometabolic interference between cancer and COVID-19

Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNγ mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+-dependent immune homeostasis

Macrophage polarization and metabolism in atherosclerosis

: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. these plaques restrict blood flow and lead to complications such as heart attack or stroke. the development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. the metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages

Prolonged exposure to simulated microgravity promotes stemness impairing morphological, metabolic and migratory profile of pancreatic cancer cells: a comprehensive proteomic, lipidomic and transcriptomic analysis

Background: The impact of the absence of gravity on cancer cells is of great interest, especially today that space is more accessible than ever. Despite advances, few and contradictory data are available mainly due to different setup, experimental design and time point analyzed. Methods: Exploiting a Random Positioning Machine, we dissected the effects of long-term exposure to simulated microgravity (SMG) on pancreatic cancer cells performing proteomic, lipidomic and transcriptomic analysis at 1, 7 and 9 days. Results: Our results indicated that SMG affects cellular morphology through a time-dependent activation of Actin-based motility via Rho and Cdc42 pathways leading to actin rearrangement, formation of 3D spheroids and enhancement of epithelial-to-mesenchymal transition. Bioinformatic analysis reveals that SMG may activates ERK5/NF-κB/IL-8 axis that triggers the expansion of cancer stem cells with an increased migratory capability. These cells, to remediate energy stress and apoptosis activation, undergo a metabolic reprogramming orchestrated by HIF-1α and PI3K/Akt pathways that upregulate glycolysis and impair β-oxidation, suggesting a de novo synthesis of triglycerides for the membrane lipid bilayer formation. Conclusions: SMG revolutionizes tumor cell behavior and metabolism leading to the acquisition of an aggressive and metastatic stem cell-like phenotype. These results dissect the time-dependent cellular alterations induced by SMG and pave the base for altered gravity conditions as new anti-cancer technology

Impact of COVID-19 Pandemic on Children and Adolescents with Neuropsychiatric Disorders: Emotional/Behavioral Symptoms and Parental Stress

The objective of our study was to evaluate the impact of the COVID-19 pandemic on the emotional and behavioral symptoms in minors with neuropsychiatric disorders and on parental stress through a standardized neuropsychological assessment, comparing the data collected before the pandemic with those collected during the lock-down. Another goal of our study was to analyze the relationship between parental stress and behavioral/emotional symptoms in children. Our study was conducted on 383 families of patients who had already been referred at the Child Neuropsychiatry Unit of the University Hospital of Salerno for different neuropsychiatric conditions. All the parents completed two neuropsychological standardized questionnaires for the assessment of parental stress (PSI—Parenting Stress Index-Short Form) and the emotional/behavioral problems of their children (Child Behaviour CheckList). The data collected during the pandemic were compared with those collected from questionnaires administered during the six months preceding the pandemic, as is our usual clinical practice. The comparison between the mean scores of PSI and CBCL before and after the pandemic showed a statistically significant increase in all subscales analyzed in the total sample. The correlation analysis showed significant positive relationship between the subscale Total Stress of PSI and the subscales Total Problems and Internalizing Problems of CBCL. Our study suggested that the COVID-19 pandemic and the corresponding measures adopted led to an increase in internalizing and externalizing symptoms in children and adolescents with neuropsychiatric disorder. Similarly, parental stress increased during COVID-19 and ahigher level of stress in parents can be related to the internalizing symptoms of their children

Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages

BackgroundA bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.MethodsTHP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.ResultsHigher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+and CD8+IFNγ+effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.ConclusionsTaken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies