Citations

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Introduction There is no prospective data to guide the utilization of peri-transplant radiation (PTRT) in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). In retrospective analyses, PTRT has been associated with local disease control, however evidence supporting improved progression free survival (PFS) is less well defined (Milgrom SA et al Cancer. 2017; 123(8):1363-1371). Furthermore, the added benefit of PTRT in the era of recent advancement in salvage strategies, including brentuximab vedotin (BV) and checkpoint inhibitors (CPI), is unclear. In a multicenter, retrospective analysis, we evaluated the impact of PTRT on PFS for patients with R/R cHL. Methods We identified consecutive pts ≥7 years old at time of diagnosis with R/R cHL treated with autologous stem cell transplant (ASCT) at 5 US academic institutions between 2010-2021. PTRT was defined as radiation administered within 3 months of ASCT. The primary objective was to compare the post-ASCT PFS, defined as the time from ASCT to subsequent relapse or death from any cause, between the two groups. Univariable and Multivariable Cox regression was performed to evaluate the impact of various relevant clinical factors on post-ASCT PFS. Results A total of 958 eligible pts were identified ( Table 1). The median age at cHL diagnosis was 31 (range, 7-72). At the time of first relapse/primary refractory disease, 406 (54%) pts had early-stage disease, 167 (24%) pts had bulky disease (≥5.0 cm), 308 (36%) pts had extra-nodal disease, 182 (22%) pts had B-symptoms (B-sx), and 338 (45%) had primary refractory disease. A total of 302 (32%) pts received >1 line of salvage before ASCT. Salvage treatment at any time point before ASCT included chemotherapy only for 457 (48%) patients, BV(+/- chemotherapy) for 308 (32%) patients, and CPI (+/- BV or +/- chemotherapy) for 193 (20%) patients. In total, 239 (24.9%) pts received PTRT, 139 (58.1%) before ASCT and 100 (41.8%) after ASCT. Among pts with available dosing information (23.3%), the median radiation dose administered was 28 Gy. The most common doses administered were 30 Gy in 77 (31.7%) pts, 36 Gy in 62 (27.8%) pts, and 18 Gy in 43 (19.2%) pts. Radiated sites included mediastinum in 172 (80.7%) pts, neck/cervical lymph nodes in 68 (31.9%) pts, and supra/infra clavicular region and axilla, each in 31 (14.6%) pts. Compared to the 719 pts that did not receive PTRT, patients treated with PTRT were more likely to have early stage disease (73% vs 47%, p<0.001), bulky disease (30% vs 22%, p = 0.048), primary refractory disease (56% vs 40%, p <0.001), >1 line of salvage treatment prior to ASCT (40% vs 29%, p<0.001), and <CR prior to ASCT (36% vs 27%, p = 0.007) (Table 1). Patients treated with PTRT were less likely to have RT at initial diagnosis (5.9% vs 22%, p<0.001), extra-nodal disease (19% vs 42%, p<0.001), B-sx (17% vs 25%, p=0.035), salvage treatment that included CPI (11% vs 23%, p<0.001), and BV maintenance (20 vs 31%, p<0.001). After a median follow up from ASCT of 4.5 years (range, 2.4-7.2), 2-year PFS was 76% (73%, 79%) and 5-year PFS was 70% (67%, 73%). In univariable analysis, receipt of PTRT showed non-significant reduced hazard for PFS (HR 0.79, 95% CI 0.59-1.05, p = 0.093) (Figure 1). In a multivariable model, PTRT showed significant association with PFS (HR 0.56, 95% CI 0.36-0.88, p=0.009) when adjusting for other clinically relevant factors at relapse such as stage, B-sx, bulk, primary refractory disease, BV(+/- chemotherapy) or CPI (+/- BV or +/- chemotherapy) in salvage, PET response prior to ASCT, and BV maintenance after ASCT. To determine if specific subgroups benefited from PTRT, we tested for interaction effects between PTRT and clinically relevant factors. Only bulk (HR 0.37, 95% CI 0.16-0.85, p=0.013) and B-sx (HR 0.45, 95% CI 0.20-1.02, p=0.041) showed significant interaction with PTRT.Among pts with bulky disease, 5-year PFS was significantly improved with receipt of PTRT (81% vs 62%, p=0.013). Conclusion In this large multi-center analysis of pts with R/R cHL undergoing ASCT, there was no significant difference in PFS regardless of receipt of PTRT. However, after adjusting for known clinically relevant factors, receipt of PTRT was significantly associated with PFS and was particularly beneficial for patients with bulky disease or B-sx at relapse. We found decreased utilization of PTRT in pts receiving CPI-based salvage; therefore the role for PTRT for pts receiving CPI-based salvage is unclear.

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN >7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

Background: For patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (HL), the standard of care remains salvage therapy followed by autologous stem cell transplant (ASCT) for responding patients. Historical data suggest 40% of patients may relapse after ASCT, and these patients have generally a poor median overall survival (OS) of less than 2 years (Moskowitz et al., Br J Haematol. 2009;146(2):158-62). However, since these reports, the treatment landscape of R/R HL has dramatically improved, most notably with the introduction of two novel therapies, brentuximab vedotin (BV) and anti-PD1 agents. To refine our understanding of clinical outcomes in this context, we characterized patients who relapsed after ASCT in the modern era. Methods: We used a multicenter retrospective patient database at 5 transplant centers in the United States to identify patients with HL aged ≥ 12 years at diagnosis who had received ASCT on or after 1/1/2010. The primary objective was to determine the median OS for patients who relapsed after ASCT (post-ASCT-relapse OS), defining survival as the time from relapse after ASCT to subsequent death from any cause. Univariable Cox regression was performed to evaluate the impact of various factors on post-ASCT OS. Outcomes by era were evaluated using three different eras based on approval dates of novel agents: (1) pre-BV approval (pre-7/31/2011), (2) post-BV approval (8/1/2011-4/30/2016), (3) post-anti-PD1 approval (5/1/16-present). Results: A total of 215 patients were identified. The median age at ASCT was 34. Before ASCT, 128 patients (62%) had no exposure to novel agents, 76 patients (35%) had received BV and no anti-PD-1 therapy, and 11 patients (5.1%) had received anti-PD-1 therapy with or without BV. Conditioning was mostly with BEAM (59%) or CBV (32%). The median time to relapse after ASCT was 6 months (range: 1-109 months). Nearly half all relapses (47%) occurred within 6 months of ASCT. Only 14% of relapses occurred after 1 year. Among 126 patients with available treatment information, the median number of post-ASCT lines of therapy was 2 (IQR: 1, 4). Therapy for post-ASCT relapse included BV and no anti-PD-1 therapy in 41 patients (29%), anti-PD-1 therapy with or without BV for 70 patients (50%), and no novel agents for only 15 patients (11%). The median followup time from the date of ASCT among survivors was 5.0 (IQR: 2.8, 7.8) years. The median post-ASCT-relapse OS was not reached ( Figure 1). The 2- and 5-year post-ASCT-relapse OS were 75% (95% CI: 70%-81%) and 59% (95% CI: 53%-67%), respectively. On univariable Cox regression for post-ASCT-relapse OS ( Table 1), time to relapse greater than 6 (HR 0.55, 95% CI 0.35-0.85) or 12 months (HR 0.53, 95% CI 0.29-0.96) were significantly associated with improved post-ASCT-relapse OS. Increasing age at relapse was associated with worse OS (HR 1.05, 95% CI 1.04-1.07). Receipt of a novel agent (compared to chemotherapy alone) as the first salvage regimen for post-ASCT relapse was associated with improved post-ASCT OS (BV: HR 0.43, 95% CI 0.20-0.96; anti-PD-1: HR 0.44, 95% CI 0.18-1.08). Outcomes improved over time as regulatory approvals for novel agents occurred (post-BV-approval: HR 0.70, 95% CI 0.39-1.24; post-anti-PD-1 approval: HR 0.45, 95% CI 0.23-0.91). Conclusion: We show prolonged overall survival post-ASCT relapse compared to historical data likely due to the introduction of BV and anti-PD1 agents. This report represents one of the largest datasets of post-ASCT relapse in cHL, and this data should serve as an updated benchmark for future evaluations.

The single-cell platform mass cytometry (CyTOF) enables detection of significant changes in one million of renal cells, especially in subsets of immune cells in ischemic human kidneys distal to renal artery stenosis (RAS). We found that pro-repair cell types such as scattered tubular-progenitor-like cells, aged neutrophils, and regulatory B cells show a compensatory increase in RAS. Immune cell phenotype changes may reflect ongoing inflammation and impaired immune defense capability in the kidneys.

Abstract Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2′-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Abstract Introduction Immune checkpoint (IC) targeting is an attractive way to combat atherosclerosis, since ICs regulate the immune response by activating or inhibiting inflammatory pathways. We have shown that ICs exert cell-divergent functions and that cell-specific IC-based treatments can limit immune-related side effects. To design tailored IC-based immunotherapies for atherosclerosis, a detailed single-cell atlas of IC expression during atherogenesis is required. Purpose To obtain cell-type- and atherosclerosis-stage-specific expression profiles of ICs and assess the transcriptome of IC+ cells during atherosclerosis. Methods ApoE-/- mice were fed normal chow diet (NCD) for 10, 20 or 30 weeks, or high-cholesterol diet (HCD) for 6, 10, 14 (study 1) or 20 weeks (study 2). Using mass-cytometry by time of flight (CyTOF), we assessed the cell-type-specific aortic expression of ICs during atheroprogression (study 1). Using cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), we assessed the transcriptome of aortic IC+ and IC- cells (study 2). Results Using CyTOF, we identified 21 immune cell clusters, including T and B cells, Ly6C- and Ly6C+ monocytes and macrophage (mφ) subsets. On T cell subsets, IC expression remained relatively constant in early plaques independent of the type of diet, apart from an increase in CD40-CD40L and decrease in CD28 and PD-L1 in HCD-fed mice. In advanced plaques from NCD-fed mice, most T cell subsets showed increased PD-L1, GITRL and CD27, while in HCD-fed mice, CD40L was decreased and PD-L1, PD-L2, CD27, CD86-CD28 and GITR-GITRL were induced on these T cell subsets. On myeloid cells, IC expression changed during early atherogenesis. Specifically, in NCD-fed mice, CD11c+MHCII+ mφ upregulated CD40 and PD-L1 and downregulated CD27 and PD-L2, while dendritic cells increased GITR and decreased PD-L2. Additional ICs, such as GITRL, CD40L and CD86-CD28, were induced in advanced plaques from NCD-fed mice. In HCD-fed mice, numerous ICs, i.e. CD40-CD40L, GITR-GITRL, CD86-CD28 and PD-L2, were increased in myeloid subsets in both early and advanced plaques. Using CITE-Seq, we further studied ICs that were strongly regulated during atherogenesis, e.g. GITR. Gene Ontology enrichment analysis of GITR+ and GITR- cells within the myeloid and T cell subsets identified the regulation of various pathways: When compared to their GITR- counterparts, both CD25- and CD25+ CD4+GITR+ T cell subsets showed upregulated pathways of death receptor activity, while CD25+ cells also showed induction of pathways involved in transmembrane lipid transporter activity. In mφ, GITR+ mφ showed upregulated pathways of cell adhesion and cytokine activity compared to GITR- mφ. Conclusion We have identified the expression pattern of numerous ICs on aortic immune cell subsets at various atherosclerosis stages. These data will pave the way towards the development of selective IC-based therapies to combat atherosclerosis.

Abstract Background The co-stimulatory CD40–CD40 ligand axis is central in atherogenesis. Upon activation, CD40 recruits tumor necrosis factor receptor-associated factors (TRAFs) to induce downstream signaling. Murine studies with mutated CD40-TRAF binding sites in macrophages have shown that the CD40-TRAF6, rather than CD40-TRAF2/3/5, axis is crucial for atherosclerosis. We thus synthesized the small molecule inhibitor TRAF-STOP 6877002, that selectively blocks CD40-TRAF6 signaling. 6877002 successfully reduced the onset and development of atherosclerosis by reducing monocyte recruitment and macrophage activation in ApoE-/- mice without having immunosuppressive side effects. Purpose To assess whether 6877002 is a suitable candidate to pass the translational pipeline towards a clinical application. Methods Elaborate in vitro and in vivo assays evaluating the pharmacological properties and potential toxicity of 6877002. Results Together with Cyprotex, we performed in vitro assays examining the ADME profile of 6877002. In an intestinal permeability assay, 6877002 had low to moderate resorption with no significant efflux, suggesting it is not a substrate for the efflux transporters Pgp/BCRP or MRP2. A plasma protein binding assay showed very low unbound 6877002 fractions, indicating that it is highly bound to plasma proteins. The potential to inhibit cytochrome P450 enzymes was assessed using human liver microsomes in the presence of enzyme-specific probe substrates. While 6877002 inhibited CYP1A2 (IC50=4.01 µM), no potential for inhibiting other CYP isoforms was detected, suggesting low drug-drug interaction potential. To screen for putative cardiovascular risks, hERG ion channel inhibition was assessed and no IC50 could be determined. Hepatic clearance was rapid in mice, rats and dogs, while minipig and human hepatocytes had lower intrinsic clearance. Together with Aptuit, we developed suitable formulations for oral and i.v. administration. In vivo pharmacokinetics studies in rats showed low bioavailability (8.43%) and rapid clearance of orally administered 6877002 compared to i.v. injected 6877002, likely – and in line with our in vitro data – due to fast first-past effect in mouse hepatocytes and uptake by macrophages. To explain the high efficacy of 6877002 despite its rapid metabolism, we assessed whether 6877002 has active metabolites that bind the CD40-TRAF6 pocket and performed an LC-MS/MS-based metabolite profiling. We detected 17 metabolites. Further MD simulations confirmed that Metabolite (M)4, the most abundant metabolite, binds the CD40-TRAF6 pocket, reflected by the highest binding mode (-19.6; defined as Binding Free Energy derived from 40-50 ns of MD run as compared to -16.5 for 6877002). Similar to 6877002, M4 reduced atherosclerosis by 54% in Western diet-fed ApoE-/- mice, indicative of M4 being an active metabolite. Conclusion CD40-TRAF6 inhibitors are an attractive strategy to combat atherosclerosis with high translational potential.

Abstract Background Atherosclerosis is a chronic inflammatory disease, characterized by the formation of luminal plaques in arteries. Atheroprogression is accompanied by strong immune activation, during which T cells play a pivotal role. Genes driving T-cell activation are regulated by the polycomb repressive complex 2(PRC2), whose major component is the Enhancer of Zeste Homolog 2(EZH2), responsible for the methylation of Histone 3 Lysine 27(H3K27me3) epigenetic mark. Purpose We hypothesize that EZH2 mediates T-cell activation and modulates T-helper (Th) cell polarization, thus atherogenesis. Methods To study the effect of EZH2 in atherosclerosis, we backcrossed mice with Ezh2 flanked by loxP-sites sensitive to Cre-mediated inactivation in T cells to apolipoprotein E (Apoe-/-)mice and fed a high cholesterol diet to have hyperlipidemic Ezh2fl/flCd4CreApoe-/-mice and controls. Atherosclerotic plaque progression and immune cell phenotyping were assessed by histology, flow cytometry (FC), gene and protein expression analysis and single cell (sc)RNA-sequencing (Seq) as well as by functional in vitro assays. Results T cell-specific EZH2 deficiency resulted in a significant reduction in H3K27me3 in T-cells. Female Ezh2fl/flCd4Cre mice developed 34% less atherosclerotic plaques in the aortic root compared to wildtype (WT) littermates. FC analysis of spleen and lymph nodes of Ezh2fl/flCd4Cre mice revealed a shift from naive to effector CD4+ T cells, and the majority were Th2 cells (p<0.0001). Accordingly, plasma levels of lL4 and aortic IL4 transcripts were increased in Ezh2fl/flCd4Cre mice(p=0.05 and p=0.0079, respectively). Functional analysis revealed that splenic CD4+ T cells from Ezh2fl/flCd4Cre mice showed decreased migratory capacity towards the chemokines CXCL10, CCL17, CCL22, CCL19. To unravel mechanisms driving the type 2 immune response, bulk RNA-Seq of CD4+ T cells and scRNA-Seq of splenic CD3+ T cells from Ezh2fl/flCd4Cre and WT mice revealed that CD4+ T cell EZH2 deficiency caused upregulation of promyelocytic leukemia zinc finger (Plzf), a transcription factor of NKT cells of the NKT2 subtype, characterized by high IL4 production. Via FC we confirmed the increase in splenic NKT cells in Ezh2fl/flCd4Cre mice. Likewise, Plzf aortic mRNA levels were also significantly increased(p=0.002). To exploit the translational potential of T cell-specific EZH2 targeting, we treated Jurkat T cells with EZH2 inhibitors, the FDA-approved drug Tazemetostat and GSK126. Corroborating our in vivo data, EZH2 inhibitor-treated cells showed decreased H3K27me3 and 70% reduced migration towards the chemokine CXCL12. Conclusions Our study demonstrates that CD4+ T-cell specific EZH2 deficiency impairs T cell-migration and skews the immune response towards a type 2 response, resulting in protection against atherosclerosis. We aim at investigating whether the epigenetic mark H3K27me3 in T cells may be a promising therapeutic target for future cardiovascular immunotherapies.