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Metabolic Reprogramming Driven by Ant2 Deficiency Augments T Cell Function and Anti-Tumor Immunity in Mice
No full textT cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation
First-in-Human Phase 1 Study of KHK2455 Monotherapy and in Combination With Mogamulizumab in Patients With Advanced Solid Tumors
No full textBackground: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors.
Methods: Patients received oral KHK2455 at fixed doses of 0.3, 1, 3, 10, 30, and 100 mg once daily as run-in monotherapy for 28 days (cycle 0), and then in combination with 1 mg/kg intravenous mogamulizumab given weekly for cycle 1 and every 2 weeks from cycle 2 onward.
Results: Thirty-six patients were enrolled. One patient with an initial diagnosis of lower esophageal cancer (100-mg cohort) experienced grade 3 gastrointestinal necrosis, and did not receive mogamulizumab. Overall, KHK2455 + mogamulizumab was well tolerated, with manageable adverse events at all doses. KHK2455 + mogamulizumab demonstrated dose-dependent plasma concentration increases and suppression of IDO1 activity. One patient with advanced bevacizumab-resistant glioblastoma demonstrated a durable confirmed Response Evaluation Criteria in Solid Tumors, version 1.1, partial response, and nine patients achieved a durable disease stabilization of ≥6 months. On the basis of the preliminary antitumor response, the cohort expansion was not initiated.
Conclusions: KHK2455 + mogamulizumab was safe and well tolerated with manageable toxicities, and resulted in dose-dependent suppression of IDO1 activity; signals of antitumor activity were observed
Summary of the 2024 Brano Heart Failure Forum
No full textSince 2007, the Branislav “Brano” Radovancevic Heart Failure Forum (BHFF) has been held annually to provide a venue for experts to present and discuss “Innovations and New Treatment Strategies in Heart Failure.” Clinicians and researchers gather yearly in a different Eastern European city to discuss the latest in heart failure diagnostics and therapeutics. The 2024 BHHF was held on the 18th through the 20th of September 2024 in Belgrade, Serbia. It was attended by over 100 faculty from 16 countries. In addition, participation through online streaming was available. Throughout the forum, 17 sessions focused on challenges and solutions related to mechanical circulatory support and heart transplantation. This issue of The VAD Journal presents a summary of conference events
Cetuximab Increases LGR5 Expression and Augments LGR5-Targeting Antibody-Drug Conjugate Efficacy in Patient-Derived Colorectal Cancer Models
No full textColorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warrants strategies to improve ADC efficacy. Here, we report that cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody indicated for RASWT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well tolerated and significantly inhibits tumor growth. Importantly, cetuximab in combination with LGR5 ADCs results in enhanced tumor inhibition or regression versus single-agent treatment and extends survival in RASMUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggest a broader clinical use for cetuximab in treating RASMUT CRC
Longitudinal Associations of Epigenetic Aging With Cognitive Aging in Hispanic/Latino Adults From the Hispanic Community Health Study/Study of Latinos
No full textDue to the paucity of longitudinal DNA methylation data (DNAm), especially among Hispanic/Latino adults, the association between changes in epigenetic clocks over time and cognitive aging phenotypes has not been investigated. This longitudinal study included 2671 Hispanic/Latino adults (57 years; 66% women) with blood DNAm data and neurocognitive function assessed at two visits ~7 years apart. We evaluated the associations of 5 epigenetic clocks and their between-visit change with multiple measures of cognitive aging that included a global and domain-specific cognitive function score at each visit, between-visit change in global and domain-specific cognitive function score, and MCI diagnosis at visit 2 (V2). There were significant associations between greater acceleration of all clocks and lower cognitive function at each visit and MCI at V2. The strongest associations were observed for GrimAge and DunedinPACE. There were significant associations of between-visit increase in PhenoAge and GrimAge acceleration with decline in cognitive function and greater risk of MCI diagnosis at V2. Epigenetic aging is associated with lower global and domain-specific cognitive function, greater cognitive decline, and greater risk of MCI in Hispanic/Latino adults. Longitudinal assessment of change in age acceleration for second-generation clocks, GrimAge and PhenoAge may provide additional value in predicting cognitive aging beyond a single time point assessment
Association of Epigenetic Aging With Plasma Cbiomarkers of Amyloid, Tau, Neurodegeneration, and Neuroinflammation in Hispanic/Latino Adults
No full textBackground: Blood-based biomarkers hold significant promise for the early detection and diagnosis of Alzheimer\u27s disease (AD) and other dementias. Age-related changes in blood levels of AD biomarkers are well-documented but poorly understood. Epigenetic clocks are mathematical models based on DNA methylation patterns that reflect various aspects of the multidimensional aging process. We investigated the associations of epigenetic aging with five blood-based AD biomarkers in 2656 Hispanic/Latino adults (mean age 62.5 years; 65% females) from the Hispanic Community Health Study/Study of Latinos. We used multivariable linear regression models to estimate the associations of acceleration in each of five epigenetic clocks with each biomarker in the total sample and in sex-specific strata, controlling for chronological age, sex (except in sex-stratified analyses), Hispanic/Latino background, recruitment site, risk factors, and comorbid medical conditions.
Results: There were varying strengths of association between acceleration of the clocks and the plasma biomarkers. There were significant associations of acceleration in all epigenetic clocks with higher plasma levels of neurofilament light chain (NfL) (Beta = 0.0045 to 0.0193; P = 0.022 to 4.9 × 10-15). There were significant associations of acceleration in all epigenetic clocks except DunedinPACE with higher plasma levels of amyloid beta (Aβ)40 (Beta = 0.0033 to 0.0049; P = 0.024 to 1.7 × 10-5). PC-PhenoAge acceleration was associated with all circulating biomarkers but its associations with Aβ42, Aβ42/40 ratio, and phosphorylated Tau 181 (p-Tau181) showed heterogeneity by sex. Specifically, PC-PhenoAge acceleration was associated with higher Aβ42 and p-Tau181 levels in males (Beta = 0.0066, P = 0.002 and Beta = 0.0158, P = 2 × 10-4, respectively) but not females, while it was associated with lower Aβ42/40 ratio in females (Beta = - 0.0032, P = 0.012) but not males.
Conclusions: Epigenetic age acceleration is associated with circulating biomarkers of AD in Hispanic/Latino adults. The second-generation clock PC-PhenoAge showed strong and consistent associations across all biomarkers, and thus may reflect biological processes most relevant to age-related changes in AD biomarkers. Considering sex differences in the relationship between biological aging and circulating AD biomarkers is paramount
Reevaluating Anti-Inflammatory Therapy: Targeting Senescence to Balance Anti-Cancer Efficacy and Vascular Disease
No full textModulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment\u27s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship
Escape of Kdm6a from X Chromosome Is Detrimental to Ischemic Brains via IRF5 Signaling
No full textThe role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17–20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the gene) were subjected to a 60-min middle cerebral artery occlusion (MCAO). Gene floxed females (two alleles) and males (one allele) were included as controls. Infarct volume and behavioral deficits were quantified 3 days after stroke. Immune responses including microglial activation and infiltration of peripheral leukocytes in the ischemic brain were assessed by flow cytometry. Epigenetic modification of IRF5/4 by Kdm6a/5c was analyzed by CUT&RUN assay. The demethylation of H3K27Me3 by kdm6a increased IRF5 transcription; meanwhile, Kdm5c demethylated H3K4Me3 to repress IRF5. Both Kdm6afl/fl and Kdm5cfl/fl mice had worse stroke outcomes compared to fl/y and CKO mice. Gene floxed females showed more robust expression of CD68 in microglia and elevated brain and plasma levels of IL-1β or TNF-α, after stroke. We concluded that IRF5 signaling plays a critical role in mediating the deleterious effect of Kdm6a, whereas Kdm5c’s effect is independent of IRF5
NF2 Loss-of-Function and Hypoxia Drive Radiation Resistance in Grade 2 Meningiomas
No full textBackground: World Health Organization Grade 2 meningiomas (G2Ms) often recur and resist therapies. Grade 2 meningiomas with histopathological necrosis have been associated with worse local control (LC) after radiation therapy, but the drivers and biomarkers of radiation resistance in G2Ms remain unknown.
Methods: We performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of genetic and microenvironmental factors on clonogenic survival after ionizing radiation. We performed transcriptional profiling of our in vitro model and 18 human G2M tumors by bulk RNA sequencing as well as 8 G2Ms by single nuclei RNA sequencing.
Results: NF2 loss-of-function (LOF) mutations were associated with necrosis in G2Ms (P = .0127). Tumors with NF2 mutation and necrosis had worse post-radiation LC compared to NF2 wildtype tumors without necrosis (P = .035). Under hypoxic conditions, NF2 knockdown increased radiation resistance in vitro (P \u3c .001). Bulk RNA sequencing revealed NF2- and hypoxia-specific changes and a 50-gene set signature specific to radiation-resistant, NF2 knockdown, and hypoxic cells, which distinguished NF2 mutant/necrotic patient G2Ms by unsupervised clustering. Enrichment analysis revealed downregulation of apoptosis pathway genes and upregulation of proliferation-associated genes and genes normally downregulated after UV radiation exposure in NF2-mutant/necrotic tumor cells, which were validated with functional assays.
Conclusions: NF2 LOF in the setting of hypoxia confers radiation resistance through transcriptional programs that reduce apoptosis and promote proliferation. These pathways may identify tumors resistant to radiation and represent therapeutic targets that in the future could improve LC in patients with radiation resistant G2Ms
A Targeted Gene Expression Biomarker Predicts Clinic Low-Risk Meningioma Recurrence
No full textBackground: Despite reassuring clinical and histological features, low-grade meningiomas can recur after surgery. Targeted gene expression profiling improves risk stratification of meningiomas, but the utility of this approach for clinical low-risk meningiomas is incompletely understood.
Methods: This was a multicenter retrospective cohort study of meningiomas from patients who were treated at 4 institutions from 1992 to 2023. Adult patients with newly diagnosed or recurrent World Health Organization (WHO) grade 1 meningiomas that were treated with gross total resection (GTR) or subtotal resection (STR), or newly diagnosed WHO grade 2 meningiomas that were treated with GTR, were included. A 34-gene expression biomarker and gene expression risk score (continuous from 0 to 1) was evaluated in all samples.
Results: The study cohort was comprised of 723 patients, none of which were used for discovery or training of the gene expression biomarker and 265 of which were previously unreported. There were 626 WHO grade 1 meningiomas, 490 with GTR and 126 with STR, and 97 WHO grade 2 meningiomas with GTR. Targeted gene expression profiling classified 51.3% of clinical low-risk meningiomas as molecular intermediate-risk and 9.5% as molecular high-risk. Combining the gene expression biomarker with the extent of resection revealed that 19.8% of clinical low-risk meningiomas had unfavorable local freedom from recurrence (LFFR) and overall survival (OS), including 7.1% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR (HR per 0.1 increase in risk score 1.89, 95% CI: 1.58-2.25) across all WHO grades, extents of resection, and newly diagnosed or recurrent presentations.
Conclusions: Targeted gene expression profiling can identify clinical low-risk meningiomas that are likely to recur after surgery