Abstract Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer (NSCLC), frequently relies on epigenetic plasticity to support growth, stress adaptation, and therapeutic escape. Among the chromatin mechanisms enabling this plasticity, histone variant exchange is central. Incorporation of specific variants reshapes DNA accessibility and transcriptional programs, underpinning cancer cell adaptability. VPS72, a histone chaperone shared by the SRCAP and TIP60 complexes, mediates ATP-dependent deposition of the H2A.Z-H2B dimer into regulatory chromatin, thereby promoting proliferation, lineage state, immune evasion, and treatment tolerance transcriptional programs. H2A.Z deposition is linked to aggressive malignancy; however, the contribution of VPS72 itself to LUAD progression remains undefined. Given its central role in H2A.Z loading, the VPS72-H2A.Z axis may represent a key epigenetic driver and potentially targetable vulnerability. TCGA LUAD datasets were analyzed to profile VPS72 expression, genomic correlates, and functional relevance. VPS72 was significantly upregulated relative to normal tissue and associated with greater genomic instability, higher tumor mutational burden, stronger hypoxia signatures, earlier clinical detectability, and reduced overall survival. High VPS72 expression was also observed in female patients and ever-smokers, indicating exposure-linked modulation. Functional evaluation in LUAD models showed that genome-wide CRISPR and RNAi screens identified VPS72 as a major fitness gene. shRNA-mediated VPS72 depletion reduced proliferation and Ki-67 expression, reduced colony formation, impaired migration and invasion, and abrogated anchorage-independent growth. Transcriptional profiling revealed that VPS72 loss strongly repressed MYC- and E2F-driven cell-cycle programs and disrupted metabolic pathways, including heme biosynthesis, mitochondrial respiration, calcium signaling, and hypoxia adaptation. Although H2A.Z itself is not directly targetable, VPS72 role in its deposition creates a druggable interface. To exploit this, we developed cell-permeable peptides that block the VPS72-H2A.Z interaction, which phenocopied VPS72 knockdown by inducing apoptosis and suppressing LUAD cell growth in a dose-dependent manner. Collectively, these findings identify VPS72 as a central epigenetic regulator and therapeutically actionable vulnerability in LUAD. Disrupting the VPS72-H2A.Z axis attenuates oncogenic transcriptional programs and malignant behaviors, offering a promising strategy to overcome epigenetic plasticity and treatment resistance in aggressive NSCLC. Citation Format: Xzaviar Kaymar Solone, Selim Reza, Kalpana Subedi, Nirmal Parajuli, Li Zhou, Qing-Sheng Mi. The VPS72-H2A.Z-axis is an underappreciated oncogenic vulnerability in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1926.

Regulatory T cells (Tregs) are central mediators of immune tolerance, yet within tumors they adopt specialized phenotypes that confer the potent suppression of anti-tumor immune responses. Emerging evidence indicates that this functional plasticity is not driven by genetic alterations but instead arises from dynamic and context-dependent epigenetic reprogramming. While individual epigenetic mechanisms controlling Treg development and stability have been described, how tumor-derived cues reshape Treg epigenetic states, how these programs differ across cancer types, and which features distinguish tumor-infiltrating Tregs from their peripheral counterparts remain incompletely understood. In this review, we synthesize recent advances in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA regulation that govern Treg identity and function with a particular emphasis on tumor-specific epigenetic adaptations. We highlight emerging epigenetic hallmarks of intratumoral Tregs, discuss unresolved mechanistic questions, and evaluate the therapeutic potential and limitations of targeting epigenetic pathways to selectively modulate Tregs in cancer. By integrating mechanistic, cancer-specific, and translational perspectives, this review aims to provide a conceptual framework for understanding how epigenetic regulation shapes Treg behavior in the tumor microenvironment and how it may be exploited for cancer immunotherapy.

The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism for cancer immune evasion. Nevertheless, the mechanism is poorly understood. We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), upregulated by human papillomavirus (HPV), ubiquitinates and degrades MHC-I in HPV-positive head and neck cancer (HPV+ HNC). Inhibiting MARCHF8 restores MHC-I levels on HPV+ HNC cells, suppresses tumor growth, and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment. Furthermore, Marchf8 knockout markedly increases cross talk between cytotoxic NK cells and CD8+ T cells with macrophages and enhances the tumor-killing activity of CD8+ T cells. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, further enhances tumor suppression and increases NK and T cell infiltration in mice bearing immune checkpoint inhibitor-refractory tumors. Our findings suggest that MARCHF8 could be a promising target for immunotherapy for HPV+ HNC patients.

BACKGROUND:Adalimumab is widely used for hidradenitis suppurativa (HS), but treatment durability varies and predictors of sustained benefit remain uncertain. OBJECTIVE:To identify clinical and laboratory factors associated with adalimumab treatment durability in HS. METHODS:We retrospectively studied 135 adults with HS who initiated adalimumab as first biologic therapy across three academic centers from 2013 to 2023. Outcomes were categorized as primary failure (12-24 weeks), secondary failure (24 weeks-2 years), or sustained response (>2 years) based on discontinuation for inefficacy. Predictors of treatment durability were evaluated using ordinal logistic regression. RESULTS:In univariable analyses, Hurley stage 3, higher body mass index, diabetes, and lower hemoglobin were associated with lower adalimumab durability. In the multivariable model, Hurley stage 3 remained independently associated with less favorable durability (adjusted odds ratio 0.37, 95% confidence interval 0.17-0.81). Comorbid psoriasis was not significantly associated with durability (adjusted odds ratio 2.84, 95% confidence interval 0.96-8.39). Baseline laboratory parameters, including leukocyte and monocyte counts and albumin, did not predict outcome. Age at disease onset, disease duration, and other demographic characteristics were also not associated with durability. CONCLUSION:Hurley stage 3 was independently associated with lower adalimumab durability, while routinely available laboratory measures did not identify additional predictors of long-term treatment outcome.

The success of cancer vaccines relies on the ability of dendritic cells (DCs) to efficiently prime cytotoxic CD8 T cell responses against tumors. However, in solid tumors this process is often undermined by tumor-driven immunosuppression and intrinsic defects in DC activation. Among the signaling pathways implicated in DC dysfunction, β-catenin signaling has emerged as a key regulator of immune tolerance in DCs. In parallel, inhibitory receptors such as PD-L1 and TIM-3 on DCs have been recognized as critical DC-intrinsic brakes on CD8 T cell priming and on responses to immune checkpoint blockade (ICB). Recent work has identified a DC-intrinsic immunoregulatory circuit in which β-catenin activation in DCs-particularly in cross-presenting cDC1s-induces expression of TIM-3, thereby suppressing CD8 T cell cross-priming and limiting anti-tumor CD8 T cell immunity. This β-catenin-TIM-3 axis represents a previously underappreciated layer of negative regulation that may help explain, at least in part, the limited efficacy of many current DC-based cancer vaccines. In this review, we examine how β-catenin activation in DCs, particularly in cDC1s, induces TIM-3 and related inhibitory programs that suppress cross-priming of tumor antigen-specific CD8 T cells and constrain the efficacy of DC-based vaccines. We further discuss how selectively targeting this β-catenin-TIM-3 checkpoint axis-alone or together with PD-L1 and other β-catenin-linked receptors-could restore DC function and inform rational combinations of DC-based vaccination with ICB and other T cell-based immunotherapies.

The human leukocyte antigen (HLA) region is highly diverse and plays a crucial role in immune regulation and antigen presentation. Accurate HLA typing is essential for understanding disease susceptibility, transplantation compatibility, and pharmacogenetics. However, its application in African descent populations is challenging due to complex linkage disequilibrium patterns and the lack of ancestry-matched populations in HLA reference panels. Here, we leveraged the latest whole-genome sequencing (WGS) data from UK Biobank African individuals to perform better HLA genotyping, and further utilized allelic and haplotypic data to explore population genetics patterns of this region. With WGS-inferred HLA alleles, we identified specific admixture patterns (predominant West and East African and minor European ancestries) within British African population, revealing their complex evolutionary history. Not only did we reveal the genetic diversity within this population, but also highlighted its differences from African Americans, ancestral Africans, and other global populations. We further identified regional ancestry differences in the HLA genomic region, highlighting discordance between global and local admixture estimates. British Africans also presented unique HLA frequency distributions for both typical and disease-associated alleles or haplotypes. These findings emphasize the need for expanding African-specific HLA reference panel and prove better HLA typing can be achieved by coupling sequencing technologies with computational approaches. The HLA genetic characteristics observed in British Africans provide valuable insights into population-specific immune responses and susceptibility. Overall, this study advances our understanding of HLA diversity and genetic admixture in British African population, with important implications for both disease mechanism and clinical utility.

Alveolar macrophages (AMs) are immune cells located in the alveoli—the tiny air sacs in the lungs where gas exchange occurs. Their functions are regulated by various epigenetic mechanisms, which are essential for both healthy lung function and disease development. In the lung’s microenvironment, AMs play critical roles in immune surveillance, pathogen clearance, and tissue repair. This review examines how epigenetic regulation influences AM functions and their involvement in lung diseases. Key mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, regulate gene expression in response to environmental signals. In healthy lungs, these modifications enable AMs to quickly respond to inhaled threats. However, when these processes malfunction, they could contribute to diseases such as pulmonary fibrosis, COPD, and pulmonary hypertension. By exploring how epigenetic changes affect AM polarization, plasticity, and immune responses, we can gain deeper insights into their role in lung diseases and open new avenues for treating and preventing respiratory conditions. Ultimately, understanding the epigenetic mechanisms within AMs enhances our knowledge of lung immunology and offers potential for innovative interventions to restore lung health and prevent respiratory diseases.

Bone marrow-derived multipotent hematopoietic progenitors seed the thymus and generate early thymic progenitors (ETPs). However, the factors governing ETP formation remain poorly defined. Using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), we dissected the heterogeneity of transcriptomic and chromatin accessibility landscapes in murine ETPs. Whereas Tcf1- ETPs exhibited higher proliferative capacity, Tcf1+ ETPs appeared to be immediate, more robust precursors to T lineage-specified early thymocytes. Prethymic ablation of Tcf1 and its homolog Lef1 severely impaired ETP formation in vivo. Whereas ablating Tcf1 alone had limited impact, loss of both Tcf1 and Lef1 impaired transcriptional activation of Notch1 and Notch pathway effector molecules, including Hes1 and Hhex, accompanied by aberrantly induced B cell and myeloid gene programs. Acute deletion of both factors compromised Notch pathway, glycolysis, and T cell gene programs in emergent ETPs ex vivo. Thus, Tcf1 and Lef1 act upstream of the Notch pathway, functioning as prethymic initiators of ETP fate and intrathymic gatekeepers of ETP identity and T lineage potential.

Introduction:Idiopathic pulmonary fibrosis is a progressive lung disease with a poor prognosis. Alveolar macrophages (AMs) are essential for maintaining lung homeostasis and play a significant role in the development of lung fibrosis. Tissue-Resident Alveolar Macrophages (TR-AMs), which originate from embryonic progenitors, can self-renew locally in a steady state, independent of hematopoiesis. During fibrogenesis, circulating monocytes rapidly migrate into the lungs and differentiate into monocyte-derived AMs (Mo-AMs). MicroRNAs (miRNAs), small non-coding RNAs, are critical for regulating gene expression. Our recent study found that the loss of miRNAs in embryonic progenitors significantly decreased the number of TR-AMs in late-stage embryos, indicating that miRNAs are necessary for TR-AM development. However, the role of miRNAs in the postnatal maintenance of TR-AMs and Mo-AMs, as well as their function in pulmonary fibrosis, remains unclear. Methods and Results:Here, we demonstrate that deleting miRNAs after birth severely disrupts TR-AM homeostasis and Mo-AM repopulation from the bone marrow following irradiation. The deficiency of miRNAs in TR-AMs and Mo-AMs was linked to diminished bleomycin-induced experimental lung fibrosis. Mechanistically, the absence of miRNAs increased TR-AM apoptosis under both normal and fibrotic conditions. RNA sequencing (RNA-seq) analysis revealed distinct transcriptomic and pathway changes in miRNA-deficient AM subgroups after lung injury. The integration of RNA-seq and miRNA array analyses identified miRNA-mRNA networks in TR-AMs and Mo-AMs in response to bleomycin injury. Ingenuity Pathway Analysis further predicted let-7a, miR-155, and miR-125 as unique upstream regulators of Mo-AM responses to lung fibrosis. Conclusions:Our findings suggest that miRNAs are key epigenetic mediators that differentially regulate the maintenance and function of TR-AMs and Mo-AMs in the pathogenesis of pulmonary fibrosis.

The tumor microenvironment (TME) factors promote regulatory T cells (Treg) stability and function, but detailed epigenetic mechanisms for this regulation remain unclear. The vacuolar protein sorting-associated protein 72 homolog (VPS72), a H2A.Z chaperon protein, is highly expressed in various tumors and positively correlated with tumor progression, and TME Treg from cancer patients expressed significantly higher VPS72 than peripheral blood Tregs. To investigate the role of VPS72 in TME Treg regulation, we generated Treg-specific (VPS72-TregKO) and inducible (VPS72-TregiKO) VPS72 KO mice. In VPS72-TregKO mice, peripheral Tregs differentiation and function were severely interrupted, leading to lethal multi-organ autoimmune diseases. Bulk RNA-seq analysis confirmed the critical roles of VPS72 in Treg differentiation, homeostasis, and function. In the B16 melanoma model, VPS72-TregiKO mice exhibited significantly reduced tumor growth and progression. scRNA-seq analysis of the TME immune landscape revealed increased cytotoxic T infiltration, decreased MDSCs, enhanced T cell anti-tumor activities, and elevated DC antigen presentation and immunogenicity in VPS72-TregiKO mice. Overall, VPS72 play an essential role in Treg stability and functionality in the TME, making it a potential novel target for cancer immunotherapy. Detailed TME factors and epigenetic mechanisms on VPS72 mediated Treg regulation are currently under investigation. NIH/NCI R01 CA284740-01 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

BACKGROUND:Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with a greater prevalence and disease burden in patients who identify as African American and those with a family history of HS, suggesting a strong genetic component to its pathogenesis. OBJECTIVES:To evaluate the relationship between plasma inflammatory protein expression, HS disease severity and genetic ancestry in a diverse cohort of patients with HS. METHODS:We performed a case-control, single-centre study of patients with HS and age-, sex- and ethnicity-matched healthy control participants. We profiled circulating inflammatory proteins using Olink® high-throughput proteomics and determined genetic ancestry from whole-genome sequencing data. RESULTS:Using linear regression, we identified novel proteins associated with HS, after adjusting for age, sex and ethnicity. Our analysis also revealed differences in the inflammatory proteome linked to disease severity. Specifically, we found that plasma levels of interleukin (IL)-6 can distinguish between different Hurley stages, indicating that IL-6 may serve as a marker of disease severity. Additionally, we found variations in inflammatory protein levels based on genetic ancestry: patients with predominantly African ancestry exhibited higher levels of inflammatory proteins associated with neutrophilic inflammation, while those with predominantly European ancestry showed increased levels of T helper 1-related inflammatory proteins. CONCLUSIONS:Although we were unable to account for treatment status or comorbidities that may influence the level of inflammatory cytokines, genetic ancestry and disease severity may influence the plasma inflammatory profile in patients with HS.

Glycogen synthase kinase-3 (GSK-3)—particularly the GSK-3β isoform—plays a pivotal role in regulating dendritic cell (DC) functions, including maturation, cytokine production, and antigen presentation. In immature DCs, GSK-3β is continuously active, and its inhibition has been shown to enhance DC maturation and function. As a key upstream kinase of β-catenin, GSK-3 inhibition activates β-catenin in both human and murine DCs—a pathway traditionally linked to its immunomodulatory effects. However, our recent findings challenge this paradigm by uncovering β-catenin-independent, dual roles of GSK-3β in DCs. Our study reveals that while GSK-3β enhances DC-mediated cross-priming of CD8 T cells, it concurrently impairs the generation of memory CD8 T cells. These findings have significant implications for vaccine development and cancer immunotherapy, where both effective T-cell priming and durable memory responses are critical. This mini-review provides an in-depth analysis of mechanistic insights into GSK-3β’s paradoxical functions and discusses potential strategies to fine-tune GSK-3 activity for optimized immunotherapeutic outcomes.