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The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune‐driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence‐related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging. [ABSTRACT FROM AUTHOR]

Background and Aims: Malnutrition is common in acutely ill geriatric patients, worsening immune function and clinical outcomes. Immunonutrition, containing nutrients like omega-3 fatty acids, arginin and glutamine, may improve recovery in this population. This study aimed to evaluate the impact of immunonutrition on clinical outcomes, inflammatory markers, and immune responses in frail, hospitalized older adults., Methods: This is a retrospective observational study. In total, 36 subjects, during hospitalization, received either an immunonutrition formula or isoproteic and isocaloric enteral nutrition. The primary outcome was the length of hospital stay (LOS), with secondary outcomes focused on inflammatory cytokines and immune parameters within a week of hospitalization., Results: Patients were primarily oldest-old, with a mean age of 88.6 years ± 4.9 (range 79-96). The immunonutrition group had a significantly shorter LOS (11.37 ± 4.87 vs. 16.82 ± 10.83 days, p = 0.05) and showed increases in key cytokines (G-CSF, INF-α2, IL-12p70, IL-15, IL-2, and IL-3, p < 0.05) enhanced immune function. A decrease in T cells and an increased B/T cell ratio was also observed. No significant differences in infection rates or 90-day survival were found., Conclusions: Enteral immunonutrition improved clinical outcomes by reducing LOS and modulating immune responses in frail patients, suggesting potential benefits in recovery. Further studies are needed to confirm these findings.

The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Telomeres undergo a progressive shortening process as individuals age, and it has been proposed that severely shortened and dysfunctional telomeres play a role in the aging process and the onset of age-related diseases in human beings. An emerging body of evidence indicates that the shortening of telomeres in cultured human cells is also influenced by other replication defects occurring within telomeric repeats. These abnormalities can be detected on metaphase chromosomes. Recent studies have also identified a set of serological markers for telomere dysfunction and DNA damage (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase). With this study, the correlation between telomere abnormalities (by FISH) and these biomarkers as measured in blood serum (by ELISA) from a cohort of 22 healthy subjects at different ages (range 26-101 years) was analyzed. A strong positive correlation between aging and the presence of aberrant telomere structures, sister telomere loss (STL), and sister telomere chromatid fusions (STCF) was detected. When serum markers of telomere dysfunction were correlated with telomere abnormalities, we found that stathmin correlated with total aberrant telomeres structures (r = 0.431, p = 0.0453) and STCF (r = 0.533, p = 0.0107). These findings suggest that serum stathmin can be considered an easy-to-get marker of telomere dysfunction and may serve as valuable indicators of aging., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

In the last decade, cell therapies have revolutionized the treatment of some diseases, earning the definition of being the "third pillar" of therapeutics. In particular, the infusion of regulatory T cells (Tregs) is explored for the prevention and control of autoimmune reactions and acute/chronic allograft rejection. Such an approach represents a promising new treatment for autoimmune diseases to recover an immunotolerance against autoantigens, and to prevent an immune response to alloantigens. The efficacy of the in vitro expanded polyclonal and antigen-specific Treg infusion in the treatment of a large number of autoimmune diseases has been extensively demonstrated in mouse models. Similarly, experimental work documented the efficacy of Treg infusions to prevent acute and chronic allograft rejections. The Treg therapy has shown encouraging results in the control of type 1 diabetes (T1D) as well as Crohn's disease, systemic lupus erythematosus, autoimmune hepatitis and delaying graft rejection in clinical trials. However, the best method for Treg expansion and the advantages and pitfalls with the different types of Tregs are not fully understood in terms of how these therapeutic treatments can be applied in the clinical setting. This review provides an up-to-date overview of Treg infusion-based treatments in autoimmune diseases and allograft transplantation, the current technical challenges, and the highlights and disadvantages of this therapeutic approaches.", Competing Interests: Declaration of competing interest The authors have no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Perfluorocarbons (PFCs) are organic liquids derived from hydrocarbons in which some of the hydrogen atoms have been replaced by fluorine atoms. They are chemically and biologically inert substances with a good safety profile. They are stable at room temperature, easy to store, and immiscible in water. Perfluorocarbons have been studied in biomedical research since 1960 for their unique properties as oxygen carriers. In particular, PFCs have been used for liquid ventilation in unusual environments such as deep-sea diving and simulations of zero gravity, and more recently for drug delivery and diagnostic imaging. Additionally, when delivered as emulsions, PFCs have been used as red blood cell substitutes. This narrative review will discuss the multifaceted utilization of PFCs in therapeutics, diagnostics, and research. We will specifically emphasize the potential role of PFCs as red blood cell substitutes, as airway mechanotransducers during artificial placenta procedures, as a means to improve donor organ perfusion during the ex vivo assessment, and as an adjunct in cancer therapies because of their ability to reduce local tissue hypoxia., Competing Interests: Disclosure: M.D.N. is an advisory board member for Eurosets, Medolla Modena, Italy. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Humans can be exposed to endocrine disruptors (EDs) in numerous ways. EDs can interfere with endogenous hormones at different levels, resulting in numerous adverse human health outcomes, including immunotoxicity. In this regard, this study aimed to investigate in vitro the possible effects of EDs on immune cells and possible gender differences. Peripheral blood mononuclear cells from healthy humans, both males and females, were exposed to 6 different EDs, namely atrazine (herbicide), cypermethrin (insecticide), diethyl phthalate (plasticizer), 17α-ethynylestradiol (contraceptive drug), perfluorooctanesulfonic acid (persistent organic pollutant), and vinclozolin (fungicide). We evaluated the effect of EDs on RACK1 (receptor for activated C kinase 1) expression, considering it as a bridge between the endocrine and the immune system, and putatively used as screening tool of immunotoxic effects of EDs. The exposure to EDs resulted at different extent in alteration in RACK1 expression, pro-inflammatory activity, natural killer lytic ability, and lymphocyte differentiation, with sex-related differences. In particular, diethyl phthalate and perfluorooctanesulfonic acid resulted the most active EDs tested, with gender differences in terms of effects and magnitude. The results from our study evidenced the ability of EDs to directly affect immune cells., (© 2023. The Author(s).)

Comirnaty (BNT162b2) and Spikevax (mRNA-1273) COVID-19 vaccines encode a full-length SARS-CoV-2 Spike (S) protein. To evaluate whether the S-protein expressed following treatment with the two vaccines differs in the real-world context, two cell lines were treated for 24 h with two concentrations of each vaccine, and the expression of the S-protein was evaluated using flow cytometry and ELISA. Vaccines were obtained from three vaccination centers in Perugia (Italy) that provided us with residual vaccines present in vials after administration. Interestingly, the S-protein was detected not only on the cell membrane but also in the supernatant. The expression was dose-dependent only in Spikevax-treated cells. Furthermore, the S-protein expression levels in both cells and supernatant were much higher in Spikewax-than in Comirnaty-treated cells. Differences in S-protein expression levels following vaccine treatment may be attributed to variations in the efficacy of lipid nanoparticles, differences in mRNA translation rates and/or loss of some lipid nanoparticles' properties and mRNA integrity during transport, storage, or dilution, and may contribute to explaining the slight differences in the efficacy and safety observed between the Comirnaty and Spikevax vaccines.

B-acute lymphoblastic leukemia (B-ALL) is one of the most common pediatric cancers, wherein regulatory T cells (Treg) and exhausted CD8 + T cells may be important in its development and maintenance. In this bioinformatics study, we evaluated the expression of 20 Treg/CD8 exhaustion markers and their possible roles in patients with B-ALL. The mRNA expression values of peripheral blood mononuclear cell samples from 25 patients with B-ALL and 93 healthy subjects (HSs) were downloaded from publicly available datasets. Treg/CD8 exhaustion marker expression was normalized with that of the T cell signature and correlated with the expression of Ki-67, regulatory transcription factors (FoxP3, Helios), cytokines (IL-10, TGF-β), CD8 + markers (CD8α chain, CD8β chain), and CD8 + activation markers (Granzyme B, Granulysin). The mean expression level of 19 Treg/CD8 exhaustion markers was higher in the patients than in the HSs. In patients, the expression of five markers (CD39, CTLA-4, TNFR2, TIGIT, and TIM-3) correlated positively with Ki-67, FoxP3, and IL-10 expression. Moreover, the expression of some of them correlated positively with Helios or TGF-β. Our results suggested that Treg/CD8 + T cells expressing CD39, CTLA-4, TNFR2, TIGIT, and TIM-3 favor B-ALL progression, and targeted immunotherapy against these markers could be a promising approach for treating B-ALL.

Ulcerative colitis (UC) and Crohn's Disease (CD) are chronic relapsing inflammatory diseases that are caused by genetic, environmental, and immune factors. Treatment strategies are currently based on symptomatic control by immunosuppression. The glucocorticoid-induced leucine zipper (GILZ), a mediator of several effects of glucocorticoids, was recently found to be secreted by goblet cells and play a role in inflammatory bowel disease (IBD). This study investigates which genes GILZ is associated with in its role in intestinal barrier functions. We examined datasets from the Gene Expression Omnibus (GEO) and ArrayExpress profiles of the gut of healthy subjects (HSs), as well as UC and CD patients. The human colonic epithelial HT29 cell line was used for in vitro validation experiments. GILZ was significantly correlated with MUC2 , TLR2 , and TLR4 . In particular, an inverse correlation was found between the GILZ and MUC2 in HS and patients with IBD, mostly in those with an active disease. Further, direct pairwise correlations for GILZ / TLR2 and GILZ / TLR4 were found in HSs and UC patients, but not in CD patients. Overall, our results reveal the crosstalk at the transcription level between the GILZ , MUC2 , and TLRs in the mucosal barrier through common pathways, and they open up new perspectives in terms of mucosal healing in IBD patients.

COVID-19, the severe acute respiratory syndrome, is one of the major emergencies that have affected health care systems. Drugs and oxygen are only partially effective in saving lives in patients with severe COVID-19, and the most important protection from death is vaccination. The widespread use of COVID-19 adenovirus-based vaccines has provided evidence for the occurrence of rare venous thrombotic events including cerebral venous thrombosis and splanchnic venous thrombosis in recipients of Vaxzevria and Jcovden vaccines and the review focus on them. One year ago, thromboses in Vaxzevria recipients have been associated with thrombocytopenia in the presence of antibodies to platelet factor 4 and have been called vaccine-induced immune thrombotic thrombocytopenia (VITT). The incidence of VITT is equal to 9-31 events per one million doses of vaccines as evaluated by health agencies worldwide and is higher in female and young vaccine recipients. More recently, by using the European EudraVigilance database, it has been demonstrated that the incidence of thrombosis in recipients of adenovirus-based vaccines is 5-10 fold higher than that of VITT and 7-12 fold higher than observed in the recipients of Comirnaty, an mRNA-based vaccine, suggesting that adenovirus-based vaccines cause not only VITT but also thrombosis without thrombocytopenia (non-VITT thrombosis). The incidence of the vaccine-dependent non-VITT thrombosis is different in the adenovirus-based vaccines and the VITT/non-VITT incidence ratio depends on the severity of thrombosis and is inversely related to the age of the recipients. The possible causes and clinical implications of non-VITT thrombosis in vaccine recipients are discussed., Competing Interests: The authors have no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. All this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, and royalties., (Copyright © 2022 Cari, Naghavi Alhosseini, Bergamo, Pacor, Pierno, Sava and Nocentini.)

Purpose: Currently, bladder cancer (BC) surveillance consists of periodic white light cystoscopy and urinary cytology (UC). However, both diagnostic tools have limitations. Therefore, to improve the management of recurrent BC, novel, innovative diagnostic tests are needed. The primary aim of this study was to determine the diagnostic performance of Bladder EpiCheck (BE) and photodynamic diagnosis (PDD) guided cystoscopy in the surveillance of high-risk BC. A secondary aim was to compare Bladder EpiCheck (BE) and PDD-guided cystoscopy findings with whose of UC to design a diagnostic algorithm that facilitates clinical decision making. PATIENTS AND METHODS: This was a prospective, blinded, single-arm, single-visit cohort study. All patients were under surveillance for high-risk non-muscle-invasive bladder cancer, and underwent cystoscopy with PDD and a BE test. Those who received a histological diagnosis were used as a reference population. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of BE, PDD-guided cystoscopy, and UC for identifying biopsy-confirmed BC lesions. The diagnostic power of the test was assessed by determining the area under the curve (AUC)., Results: Forty patients were enrolled. For BE, the AUC was 0.95, and BC recurrence was detected at a sensitivity of 100% and specificity of 90.9%. For PDD, the AUC was 0.51, with a sensitivity and specificity of 61% and 41%, respectively. BE was combined with UC to create a decision-making algorithm capable of reducing the number of follow-up cystoscopies needed., Conclusion: BE is a very accurate diagnostic tool that has the potential to be useful in the surveillance of high-risk BC patients. Especially when combined with UC, it may be used to reduce the number of cystoscopies needed throughout follow-up. Conversely, the use of PDD as a diagnostic tool in such patients should be reconsidered. However, due to the small sample size of this study, a larger prospective clinical trial should be performed to confirm findings., Competing Interests: Conflict of interest The authors declare they have no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and the absence of symptoms in the early stages makes metastasis more likely and reduces survival. To aid in the early diagnosis of ccRCC, we recently developed a method based on urinary miR-122-5p, miR-1271-5p, and miR-15b-5p levels and three controls. The study here presented aimed to validate the previously published method through its application on an independent cohort. The expression of miRNAs in urine specimens from 28 ccRCC patients and 28 healthy subjects (HSs) of the same sex and age was evaluated by RT-qPCR. Statistical analyses were performed, including the preparation of receiver operating characteristic (ROC) curves. The mean ccRCC diameter in ccRCC patients was 4.2 ± 2.4 mm. Urinary miRNA levels were higher in patients than in HSs. The data were processed using the previously developed algorithm (7p-urinary score), and the area under the curve (AUC) of the algorithm's ROC curve was 0.81 ( p -value = 0.0003), with a sensitivity of 96% and specificity of 65%. Therefore, the 7p-urinary score is a potential tool for the early diagnosis of ccRCC.

The ChAdOx1 nCoV-19 (ChA) (AstraZeneca) and Ad26.COV2.S (AD26) (Janssen) vaccines are virus-based coronavirus disease 2019 (COVID-19) vaccines used worldwide. In spring 2021, venous blood clots and thrombocytopenia were described in some vaccine recipients. We evaluated the frequency of severe adverse events (SAEs) documented in the EudraVigilance European database in young adult (18-64 years old) and older (≥65 years old) vaccine recipients up to 23 June 2021 and related them to coagulation disorders and arterial, cardiac, and nervous system events. Comparison between the frequency of SAEs and SAE-related deaths in ChA and AD26 vs. BNT162b2 COVID-19 (BNT) (Pfizer/BioNTech) vaccine recipients demonstrated: 1) ChA and AD26 recipients than BNT recipients had higher frequencies of not only SAEs caused by venous blood clots and hemorrhage, but also thromboembolic disease and arterial events, including myocardial infarction and stroke; 2) a corresponding higher frequency of SAE-related deaths. The frequency was higher in both young adults and older adults. Comparison between the frequency of SAEs and SAE-related deaths in AD26 vs. ChA recipients demonstrated in AD26 recipients: 1) lower frequency of thrombocytopenia; 2) lower frequency of SAEs in young adult recipients; 3) higher frequency of SAEs in older recipients. Interestingly, most of the venous thrombotic SAEs associated with ChA and AD26 vaccines were not associated with thrombocytopenia, suggesting that TTS (thrombosis with thrombocytopenia syndrome) is not the only type of thrombosis observed following virus-based vaccines. In conclusion, both virus-based COVID-19 vaccines show more SAEs than BNT, but the frequency of the SAE type in the different age groups differs, suggesting that the mechanisms responsible of SAEs overlap only partly., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: None declared.

The involvement of viruses and SARS-CoV-2 in autoimmune diseases is well known. The recent demonstration that ChAdOx1 nCoV-19 Covid-19 (AstraZeneca) vaccine (ChA) favors the production of anti-platelet factor 4 (anti-PF4) antibodies, blood clots, and thrombocytopenia raises the question of whether other anti-CoViD-19 vaccines favor the same patterns of events. We assessed the frequency of severe adverse events (SAEs) documented in the EudraVigilance European database up to April 16, 2021 related to thrombocytopenia, bleeding, and blood clots in recipients of ChA compared to that of recipients of the BNT162b2 Covid-19 (Pfizer/BioNTech) vaccine (BNT). ChA administration was associated with a much higher frequency of SAEs in each AE Reaction Group as compared with that elicited by BNT. When considering AEs caused by thrombocytopenia, bleeding and blood clots, we observed 33 and 151 SAEs/1 million doses in BNT and ChA recipients, respectively. When considering patients with AEs related to cerebral/splanchnic venous thrombosis, and/or thrombocytopenia, we documented 4 and 30 SAEs and 0.4 and 4.8 deaths/1 million doses for BNT and ChA recipients, respectively. The highest risk following ChA vaccination is in young people and, likely, women of reproductive age, as suggested by hypothesized scenarios. In conclusion, the immune reaction promoted by ChA vaccine may lead to not only thrombocytopenia and cerebral/splanchnic venous thrombosis but also other thrombotic and thromboembolic SAEs. These events are not favored by BNT vaccine. Our study may help in the evaluation of the benefit/risk profile of the ChA vaccine considering the epidemic curve present in a country., (Copyright © 2021. Published by Elsevier Ltd.)

Endocrine disruptors (ED) are natural and anthropogenic chemicals that can interfere with hormonal systems at different levels. As such, ED-induced alterations in hormone functions have been implicated in many diseases and pathological conditions, including adverse developmental, reproductive, neurological, cardiovascular, and immunological effects in mammals. The fact that ED may compete with several endogenous hormones for multiple receptors and pathways is not always fully considered. This results in a complex response that depends on the cellular context in terms of receptors and interacting proteins and, thus, may differ between tissues and circumstances. Microglia, neurons, and other immune cells are potential targets and still underappreciated actors in endocrine disruption. Due to the large scale of this topic, this review is not intended to provide a comprehensive review nor a systematic review of chemicals identified as endocrine disruptors. It focuses on the immune-neuro-endocrine network in ED toxicity and research gaps, using atrazine as an example to highlight this complexity and the interrelationship between the immune, endocrine, and nervous systems, and ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Galbiati, Buoso, d'Emmanuele di Villa Bianca, Paola, Morroni, Nocentini, Racchi, Viviani and Corsini.)

IgG4 subclass antibodies are expressed in alternative Th2 environments featuring high IL-10 expression, including several solid tumors such as melanoma. To induce tolerance, allergen immunotherapy mediates antibody class switching from pro-inflammatory IgE to anti-inflammatory IgG4. We previously reported that IgG4 drives allergic M2 macrophages toward tolerogenic states. Here we assessed the roles of IgG4 and macrophage activation in colorectal cancer (CRC). In this observer-blinded, case-control study, we analyzed total circulating serum IgE, IgG1 and IgG4 levels in CRC (n = 38) patients with (n = 13, TxNxM1) or without (n = 25, TxNxM0) metastasis, and in healthy donors (n = 21). Primary cultures of circulating monocyte-derived macrophages from healthy controls and CRC patients were further evaluated in their responses to stimulation with IgG1 or IgG4. We found higher absolute serum levels of IgG4 in patients with CRC. IgG4 enabled polarization of macrophages derived from CRC patients and healthy controls into alternatively-activated tolerogenic M2b phenotypes. IgG4-stimulated M2 macrophages were characterized by lower surface CD206, CD163, CD14, and CD11b expression and higher CCL-1, IL-10, and IL-6 production. IgG4 was less potent that IgG1 in triggering antibody-dependent cell-mediated phagocytosis (ADCP) of cancer cells. Further, higher z-normalized IgG4/-IgE sera level ratios correlated with the presence of metastasis ( p = .0247 and p = .0009, respectively) in CRC patients. High IgG4 in CRC synergizes with macrophages in shaping an immunosuppressive microenvironment and impairs anti-cancer effector cell functions. The shift of serum IgG4/IgE ratios toward enhanced tolerance induction in metastatic disease indicates a role for high IgG4 in disease progression and poor prognostic outcome., Competing Interests: The authors declare no potential conflicts of interest., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)