Makoto Yamagishi

Here we generated a pan-cancer spatial atlas of 400 tumours across 13 tissue types and 26 subtypes from the Asia-Pacific, a region under-represented in existing pan-cancer datasets. In a multimodal cohort we integrated single-cell spatial transcriptomics (1,999 genes) with more than 70 proteins measured in the same cells as built-in validation, alongside clinical data including ancestry, age, sex and survival. ASTRA1.0 revealed that each cancer subtype has distinct expression profiles and cellular compositions. Despite this heterogeneity, we identified eight recurrent spatial cellular neighbourhoods shared across tissue types, with macrophages as key organisers. We further developed a framework to quantify the co-localisation of FDA-approved drug targets with surrounding cell types. This framework classified tumours into four Spatial Theratope subtypes, each defined by a distinct signature of co-localised targets. The VEGF-A–PD-L1 pair, targeted by bevacizumab and atezolizumab, recurred across tumour types and neighbourhoods. Spatial Theratope subtypes and neighbourhood composition were each associated with progression-free survival (PFS) in the discovery cohort, and their combination was also associated with PFS in an independent cohort of 25 patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. The ASTRA atlas provides a community resource for nominating rational, spatially informed combination therapies across cancers.

Summary: Estimating T‐cell clonality within human T‐cell leukaemia virus type 1 (HTLV‐1)–infected cell populations may aid risk assessment and diagnosis of adult T‐cell leukaemia/lymphoma (ATL). However, direct assessment of HTLV‐1 integration‐site clonality requires genetic analyses that are costly and labour‐intensive. We developed a simple flow cytometric surrogate assay by combining the HTLV‐1 analysis system by flow cytometry (HAS‐Flow) method, which efficiently identifies HTLV‐1–infected cells, with T‐cell receptor β‐chain constant region (TRBC1/2) staining. We analysed 53 HTLV‐1–infected individuals, including asymptomatic carriers ( n = 25), patients with HTLV‐1–associated myelopathy ( n = 4) and patients with ATL ( n = 24). TRBC1/2 skewing was quantified using the dominant TRBC ratio. The dominant TRBC ratio was significantly higher in ATL than in non‐ATL cases and effectively discriminated ATL from non‐ATL cases (Area under the receiver operating characteristic curve [AUC], 0.913; 95% confidence interval, 0.803–1.000; p < 0.0001). It correlated with established markers of disease progression, including abnormal lymphocyte burden, proviral load and soluble interleukin‐2 receptor levels, as well as clonality assessed by two independent HTLV‐1 integration‐site–based methods (viral integration site and RAISING‐CLOVA). These findings indicate that assessment of TRBC1/2 skewing in HTLV‐1–infected cells (HAS‐TRBC method) is a simple, cost‐effective surrogate for estimating T‐cell clonality within HTLV‐1–infected cell populations, with potential clinical utility.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease driven by HTLV-1-infected CD4⁺ T cells; however, the phenotypic and functional characteristics of disease-associated T-cell subsets remain incompletely understood. We analyzed samples using flow cytometry (n = 3–5 per group) and RNA-seq (n = 13), focusing on CADM1^highCD4⁺ T cells enriched for HTLV-1-infected cells to evaluate a transferrin receptor (TfR)-expressing subset. TfR⁺CADM1^highCD4⁺ T cells were detected in both asymptomatic carriers and patients with HAM, but their frequency among CD4⁺ T cells was higher in HAM patients. These cells exhibited a Treg-like phenotype with higher Foxp3 and CTLA-4 expression than TfR⁻ cells and showed increased Ki-67 positivity, consistent with proliferation. Despite this phenotype, they produced interferon-γ, indicating inflammatory potential, while Foxp3 expression was lower in HAM patients than in asymptomatic carriers, suggesting a more inflammatory phenotype. Furthermore, TfR transcript levels (RNA-seq TPM) correlated with clinical indicators of disease activity, including neopterin and CXCL10 protein levels, and the Osame motor disability score. Collectively, these findings suggest that TfR identifies a proliferative, Foxp3-low, Treg-like inflammatory CD4⁺ T-cell subset that is associated with disease activity in HAM.

Human T‐cell leukemia virus type 1 (HTLV‐1) causes adult T‐cell leukemia/lymphoma (ATL) and HTLV‐1–associated myelopathy, and its viral transactivator Tax is central to disrupting host transcriptional control. Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax‐associated complexes in HTLV‐1–infected T‐cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF‐κB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co‐immunoprecipitation experiments confirmed Tax–IRF4 binding, and chromatin profiling revealed that Tax reprograms genome‐wide IRF4 occupancy. In infected T‐cells, IRF4 was enriched in super‐enhancer (SE) regions, where Tax, IRF4, and NF‐κB factors colocalized at ATL‐related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co‐expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL‐associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax‐driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV‐1–infected T‐cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection‐specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.

T-cell lymphomas are clinically and biologically heterogeneous malignancies that comprise ~ 10% of non-Hodgkin lymphomas. Outcomes with first-line chemotherapy remain poor. Over the past decade, integrative genomic and epigenomic studies have defined recurrent abnormalities converging on proximal T-cell antigen receptor/costimulatory signaling to the NF-κB/NFAT, JAK/STAT, PI3K/AKT/mTOR, and NOTCH pathways, alongside pervasive alterations in chromatin modifiers and the DNA methylation machinery. In this review, we frame the biology of peripheral T-cell lymphoma as two interdependent layers, including genetic events that establish constitutive signaling programs and epigenomic remodeling that stabilizes these outputs. We overview genomic alterations across major peripheral T-cell lymphoma entities and analyze epigenomic dysregulation, focusing on DNA methylation, enhancer regulation, and polycomb-mediated gene control. We highlight adult T-cell leukemia/lymphoma as a paradigmatic dual-layer disease, summarize therapeutic approaches based on epigenetic traits, and discuss biomarker-guided strategies and challenges in translating integrated maps into durable disease control.

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive and refractory hematologic malignancy that is caused by human T‐cell leukemia virus type‐1 (HTLV‐1) retrovirus. ATL results from a combination of viral latency and the accumulation of abnormalities throughout the genome, epigenome, transcriptome, and signaling pathways. Despite numerous studies, the data have been largely fragmentary, and a comprehensive understanding of this disease remains unclear. Recent comprehensive analyses have contributed not only to the identification of fundamental molecular abnormalities in ATL, but also to the development of novel therapeutic strategies and prognostic models. In this review, an overview of the latest advances in the genomic, epigenomic, and transcriptomic alterations associated with ATL is provided, which highlights the opportunities for clinical management of ATL. Integrated omics approaches will further increase our understanding of refractory disease and provide a foundation for designing new treatments that target core molecular drivers.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM) is a debilitating neuroinflammatory disease with no available effective treatments. A hallmark of HAM is the transformation of HTLV-1-infected cells into T helper type 1 (Th1)-like cells, characterized by excessive interferon (IFN)-γ production that drives chronic inflammation. However, the molecular mechanisms fuel this aberrant Th1-like transformation and sustained inflammation remain poorly understood. We hypothesized that HAM-characteristic chromatin remodeling plays a pivotal role in the overexpression of key genes driving inflammatory pathogenesis. Using transcriptomic analysis, chromatin accessibility profiling, and biomarker evaluations across HTLV-1-related diseases, we identify MAP3K8 as a key gene that defines the unique inflammatory profile of HAM. MAP3K8 overexpression promotes Th1-like differentiation and constitutively activates the MEK-ERK signaling pathway. Furthermore, we elucidate the mechanism by which HTLV-1 Tax, Fosl2, and c-Jun collaboratively induce HAM-characteristic chromatin remodeling at the enhancer region of the MAP3K8 locus. Crucially, we demonstrate that mitogen-activated protein kinase kinase (MEK) inhibitors effectively suppress the MAP3K8-MEK signaling cascade and significantly mitigated inflammatory pathogenesis in an ex vivo culture assay. Our findings provide critical insights into the virus-host interactions underpinning HAM and propose the MAP3K8-MEK-ERK axis as a promising therapeutic target for this challenging condition.

Human T‐cell Leukemia Virus Type 1 (HTLV‐1) is a pathogenic human retrovirus that is responsible for intractable diseases such as adult T‐cell leukemia–lymphoma (ATL), a malignancy with a poor patient prognosis. Although recent studies have delineated several genomic, epigenomic, and transcriptomic abnormalities associated with HTLV‐1, to date the importance of epitranscriptomic modifications, particularly N ⁶ ‐methyladenosine (m ⁶ A), remains unclear. Here, we showed that the HTLV‐1 RNA genome undergoes m ⁶ A modification, thereby suggesting that these modifications act as bidirectional regulators of both viral and host processes. Moreover, targeted depletion of m ⁶ A modification within the viral transactivator HTLV‐1 Tax resulted in markedly destabilized Tax mRNA, attenuated Tax protein abundance, and suppression of downstream expression of host genes including IL2RA and TXN . Overall, these findings suggest that m ⁶ A methylation is an essential determinant of the HTLV‐1 life cycle, and understanding it may offer mechanistic insight into viral latency and present novel avenues for therapeutic intervention and prophylaxis.

In adult T-cell leukemia/lymphoma (ATL), tumor cells show a regulatory T-cell (Treg)-type phenotype, which influences their tumor immunity. However, our knowledge of what molecular events are involved in pathogenesis is still missing. Here, we took advantage of this unique phenotype and screened whole transcriptome data from primary ATL cells to search for effective therapeutic targets. Glycoprotein A repetitions predominant (GARP) was identified as a novel tumor antigen in ATL. ATL cells overexpress GARP and release transforming growth factor-β (TGF-β). The GARP–TGF-β axis promotes cell proliferation of ATL cells and human T-cell leukemia virus type 1 (HTLV-1)-infected cells with changes in cell signaling activities and shaping of Treg gene expression patterns, but suppresses the activity of surrounding effector T-cells. Remarkably, this study has provided a breakthrough therapeutic concept that achieves the dual effect of direct tumor cell depletion and indirect immune activation by a single treatment targeting GARP. DS-1055a, an anti-GARP monoclonal antibody, selectively and effectively depleted malignant ATL cells via antibody-dependent cellular cytotoxicity, supporting the proof-of-concept in the preclinical study. Our findings highlight the key to understanding the cell origin of ATL and developing unprecedented therapeutic strategies for refractory diseases.

Human T-lymphotropic virus type 1–associated (HTLV-1–associated) myelopathy (HAM, also known as tropical spastic paraparesis) is a rare neurodegenerative disease with largely elusive molecular mechanisms, impeding targeted therapeutic advancements. This study aimed to identify the critical molecule responsible for neuronal damage in HAM, its source, and the regulatory mechanisms controlling its expression. Utilizing patient-derived cells and established cell lines, we discovered that HTLV-1 Tax, in conjunction with specificity protein 1 (Sp1), enhanced the expression of repulsive guidance molecule A (RGMa), a protein known to contribute to neuronal damage. RGMa expression was specifically upregulated in HTLV-1–infected cells from patients with HAM, particularly in those expressing HTLV-1 Tax. Furthermore, in CD4 ⁺ cells from patients with HAM, the level of H3K27me3 methylation upstream of the RGMA gene locus was reduced, making RGMA more prone to constitutive expression. We demonstrated that HTLV-1–infected cells in HAM inflict neuronal damage via RGMa. Crucially, the neutralizing antibody against RGMa, unasnemab (MT-3921), effectively mitigated this damage in a dose-responsive manner, highlighting RGMa’s pivotal role in neuronal damage and its potential as a therapeutic target for alleviating neuronal damage in HAM.