Cell Reports Medicine最新文献

Over the past decade, clinical trials of therapeutic cancer vaccines have evolved substantially in scope and design, renewing interest in this immunotherapy modality. Advances in sequencing technologies and an improved understanding of the tumor microenvironment have enabled precise targeting of tumor neoantigens, accelerating the development of personalized cancer vaccines. In this review, we critically evaluate the current landscape of cancer vaccines, particularly neoantigen-based approaches, in light of recent clinical trial data. Although cancer vaccines have historically demonstrated limited efficacy as monotherapies, growing evidence suggests enhanced clinical benefit when combined with other anti-cancer treatments, including immune checkpoint inhibitors. Drawing on these findings, we summarize key lessons from past efforts and highlight persistent knowledge gaps that limit broader clinical success. Finally, we discuss emerging strategies to overcome these challenges, with the aim of improving vaccine efficacy and facilitating the integration of cancer vaccines into standard-of-care treatment for cancer patients.

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy is highly effective for B cell precursor acute lymphoblastic leukemia (BCP-ALL); however, approximately half of the patients relapse. Thus, there is an urgent need to identify factors that improve efficacy. This study enrolls 19 patients with BCP-ALL (16 children and 3 young adults) who receive tisagenlecleucel. Infusion products, peripheral blood, and bone marrow samples are obtained before and after CAR-T cell infusion. Single-cell analysis reveals that central memory CAR^pos T cells increase in long-term responders, whereas CXCR3⁺CD38^highPD-1^high effector CAR^pos T cells are enriched in relapsed patients, post-infusion. By contrast, CAR^pos T cells obtained from infusion products in long-term responders are enriched in the CD38^-CD73^-Tim-3^-HLA-DR⁺ phenotype, characterized by a decreased ability to produce adenosine, memory-like transcriptomic characteristics, and leveraging of mitochondrial metabolism and oxidative phosphorylation. Our study reveals that the CD38^-CD73^-Tim-3^-HLA-DR⁺ phenotype contributes to long-term remission in patients with BCP-ALL who receive tisagenlecleucel.

Chimeric antigen receptor (CAR)-T cell therapy targeting antigens shared with normal T cells requires genetic modifications to prevent fratricide. This phase 1 trial evaluates autologous CD5-targeting CAR-T cells with CD5 gene deletion (CT125A) in seven patients with relapsed/refractory CD5⁺ hematologic malignancies. The overall response rate is 85.7%, including four complete responses. All patients experience cytokine release syndrome (six grade 1-2, one grade 3), and two patients develop immune effector cell-associated neurotoxicity syndrome. The most common grade ≥3 adverse events are cytopenia and infection, with unique observations of rash and autoimmune-related events. Post-infusion immunophenotyping shows persistent depletion of CD5⁺ T cells and CD19⁺ B cells, with reduced CD4/CD8 ratios. The human CD5 knockin murine model reveals skin lesions without significant vital organ involvement. These findings demonstrate CT125A's therapeutic potential in CD5⁺ malignancies while highlighting the need for safety optimization. The trial has been registered at ClinicalTrials.gov (NCT04767308).

Up to 20% of patients with early-stage oral squamous cell carcinoma (OSCC) develop postoperative relapse, but no parameters currently enable the identification of individuals with poor prognosis. Here, we report a spatially resolved single-cell analysis of the tumor microenvironment in OSCC. By analyzing >700,000 cells for 25 proteins using imaging mass cytometry, we discover leukocyte and endothelial cell phenotypes that are independent prognostic factors for survival. Most notably, the presence of proliferating lymphatic endothelial cells (KI67⁺PROX1⁺), which show distinct molecular signature in transcriptomic analyses, in the invasive tumor margin strongly predicts poor recurrence-free survival in early-stage OSCC. We validate our findings in an independent OSCC cohort using an easy-to-measure KI67⁺PROX1⁺ immunostaining biomarker assay and multivariate analyses of recurrence-free, disease-specific, and overall survival. Thus, our data highlight the role of tumor microenvironment in OSCC progression and its potential impact on treatment strategies.

Human respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are frequent drivers of morbidity and mortality in susceptible populations. The primary target of neutralizing antibodies is the fusion (F) glycoprotein on the surface of the RSV and hMPV virion. As a result of the structural conservation between RSV and hMPV F, three antigenic regions are known to induce cross-neutralizing responses: sites III, IV, and V. Leveraging LIBRA-seq, we identify five RSV/hMPV cross-reactive human antibodies. One antibody, RM 5-1, potently neutralizes all tested viruses from the major subgroups of RSV and hMPV and provides protection against RSV and hMPV in a mouse challenge model. Structural analysis reveals that RM 5-1 utilizes an uncommon genetic signature to bind an epitope that spans sites Ø, II, and V. These findings highlight the molecular and structural elements influencing RSV and hMPV cross-reactivity as well as the potential of antibody RM 5-1 for translational development.

In the mid-2000s, mouse studies suggested that the gut microbiome might influence energy harvest, fat storage, appetite, insulin sensitivity, and inflammation. Since then, our understanding of the gut microbiome's role in obesity has advanced significantly. Mechanistic studies identified microbial metabolites, such as short-chain fatty acids, bile acids, branched-chain amino acids, tryptophan catabolites, and imidazole propionate, as key modulators of metabolism, inflammation, and gut-brain communication. Metagenomic and multi-omics technologies now provide deeper insights into the intricate interactions between microbes, metabolites, and host factors, reshaping obesity research and reinforcing the need for phenotype stratification by recognizing microbiome-driven metabolic profiles. Integrating gut microbiome data into clinical strategies may enable targeted interventions for specific obesity subtypes, advancing prevention and personalized care. However, as new anti-obesity medications emerge, it is imperative to determine how microbiome-based therapies can complement them, considering efficacy, cost, and patient-specific variability.

From extrachromosomal DNA to neo-peptides, reprogramming of cancer genomes leads to the emergence of cancer state-specific molecules. Here, we systematically identify and characterize a large repertoire of orphan non-coding RNAs (oncRNAs), a class of cancer-emergent small RNAs, across 32 tumor types. We show that oncRNA binary presence-absence patterns represent a digital molecular barcode that captures cancer type and subtype identities. Importantly, this barcode is partially accessible from the cell-free space as cancer cells secrete a subset of oncRNAs. Leveraging large-scale in vivo genetic screens in xenografted mice, we functionally identify driver oncRNAs in multiple tumor types. In a retrospective study across 192 breast cancer patients, we show that oncRNAs are reliably detected in blood and that changes in cell-free oncRNA burden predict both short-term and long-term clinical outcomes. Together, we establish that oncRNAs have potential roles in tumor progression and clinical utility in liquid biopsies for tumor-naive minimum residual disease monitoring.

Regenerative therapies for salivary gland dysfunction remain unavailable. We establish a fully chemically defined, xeno-free three-dimensional culture system to generate functional human salivary gland organoids. These organoids recapitulate the typical glandular architecture and display multilineage cellular composition, supporting long-term expansion with high transcriptomic fidelity to the primary tissue. The organoids exhibit key salivary functions, including glycoprotein secretion, amylase expression, and calcium flux in response to cholinergic stimulation. Single-cell transcriptomic analysis reveals preserved epithelial heterogeneity within the organoids and indicates a basal-to-ductal-to-acinar bifurcated differentiation trajectory. In the orthotopic transplantation model using non-obese diabetic mice with Sjögren syndrome, the organoids significantly improve salivary secretion. In the ectopic subrenal capsule transplantation model using immunodeficient mice, the organoids achieve glandular tissue reconstruction and vascularization. This study establishes a robust, functionally mature, and clinically translatable human salivary gland organoid system as a platform for tissue regeneration therapies targeting salivary hypofunction disorders such as Sjögren syndrome.

Single-cell RNA sequencing (scRNA-seq) studies have uncovered distinct cancer-associated fibroblast (CAF) populations. While useful as a biological framework, no studies have conclusively defined CAF subtypes with clinical significance. We define restraining (rest) and promoting (pro) CAFs in patient samples that are both prognostic and predictive of therapy response in multiple tumor types. We uncover distinct clinical and spatial interactions between pro- and restCAF subtypes and basal-like and classical tumor subtypes that support tumor-stroma crosstalk. Finally, we find striking differences in the immune contexture of pro- and restCAF tumors where restCAF-dominant tumors are more responsive to immune checkpoint inhibition and proCAF-dominant tumors are more responsive to myeloid inhibition in clinical trials. This work defines CAF subtypes that are clinically robust, prognostic, and predictive of immunotherapy response and provides a single-sample classifier, determination of pro- and restCAF subtypes (DeCAF), which is clinically actionable.

Patients with liver metastases (LMs) derive less benefit from immune checkpoint blockade (ICB), yet the mechanism remains poorly understood. In the liver tumor microenvironment of patients with mismatch repair-deficient (MMR-d) cancers treated with immunotherapy, we observe a reduction of Vδ1⁺ γδ T cells. Hepatic Vδ1⁺ T cells express high levels of IFNγ at baseline compared to other organs. In patients with LMs, we identify elevated systemic IL18 levels compared to metastatic patients without LMs and find that its intratumoral expression is associated with ICB success exclusively in patients with LMs. While liver γδ T cells are specifically sensitive to IL18 stimulation ex vivo, cancer cells counteract IL18-driven immunity by secretion of IL18 binding protein (IL18BP). Blockade of IL18BP enhances interferon (IFN) γ-driven immunity against organoids in vitro. Taken together, we identify the IL18/IL18BP/Vδ1⁺ axis as an important regulator of ICB response and a therapeutic vulnerability for patients with LMs of MMR-d tumors.