Biology subjects

Prins, R.

Publications and source records attributed to Prins, R..

7 recordsLinked to original sources

bioRxiv2026

Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma

Background: Immune checkpoint inhibitors (ICI) are efficacious in many solid tumors, but response in glioma is restricted to a small subgroup. The determinants of response and resistance to ICI remain poorly understood. Methods: Here we exploit a syngeneic hypermutated high-grade glioma model with dichotomous response to combined PD-1 and CTLA-4 inhibition to unravel determinants of tumor-infiltrating T-cells driving response. Tumor-infiltrating T-cells from ICI-responsive and non-responsive tumors were analyzed by single-cell RNA and T-cell receptor sequencing and tumor-reactive T-cell receptor clonotypes were functionally validated to characterize their transcriptional phenotypes. We verify our findings in IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab. Results: ICI response was associated with intratumoral clonal expansion of tumor-reactive cytotoxic T-cells and increased infiltration of CXCR6+ CD4+ tissue resident memory T-cells (Trm). CD4 stem-like memory T-cells in responding tumors demonstrated elevated interferon responses, following trajectories toward clonally expanded Trm, versus trajectories toward exhaustion in non-responsive tumors. In responsive tumors, CD4+ Trm interacted with infiltrating CXCR3+ tumor-reactive and clonally expanded, yet transcriptionally versatile cytotoxic T-cells. Probing the post neoadjuvant ICI high-grade glioma patient tissue dataset, we confirmed increased CXCR6 expression in CD4+ T cells and the association of CD4+ Trm with prolonged overall survival. Conclusion: These findings identify CD4 tissue-resident memory T-cells as determinants of ICI response in IDH1 wildtype high-grade glioma and warrant their further investigation to improve immunotherapy outcomes.

cancer biology↗

bioRxiv2026

Chromosome-level genome assembly of Helichrysum odoratissimum, a medicinal plant from Southern Africa

Helichrysum odoratissimum, a plant species native to Southern Africa, holds deep cultural significance and is widely used in traditional medicine. It is valued for its antimicrobial and anti-inflammatory properties and is cultivated and traded in South Africa due to its growing commercial relevance to the pharmaceutical and cosmetic industries. Despite its ecological and economic importance, genomic resources for this species remain limited. Here, we report a high-quality chromosome-level genome assembly for H. odoratissimum to facilitate investigations into its genetic basis of bioactivity, environmental adaptation, and taxonomic relationships. High-molecular-weight DNA extracted from leaf tissue was sequenced using Oxford Nanopore Technologies (ONT) long-read sequencing, and Hi-C proximity ligation data were generated to enable chromosome-scale scaffolding. The final assembly spans 2.4 Gb, with a scaffold N50 of 354 Mb, and was anchored and oriented into seven chromosomes, with 2,935 smaller scaffolds remaining unplaced. Assembly quality and completeness were evaluated using QUAST and BUSCO, and chromosomal structure was validated using Hi-C contact maps. This genome provides a foundational resource for functional genomics, conservation planning, molecular breeding, and the discovery of bioactive compounds underpinning the medicinal and commercial value of H. odoratissimum.

genomics↗

bioRxiv2025

NTX250: A Modular mRNA-Based Immunotherapy Platform for HPV-Associated Cancers with Broad Applicability.

Infection with high-risk human papillomavirus (HPV) is a key driver of multiple HPV-associated malignancies, including cervical intraepithelial neoplasia (CIN), oropharyngeal, head and neck, and anogenital cancers. Despite the high efficacy of prophylactic HPV vaccines, a substantial population remains at ongoing risk due to issues related to vaccine accessibility, awareness, or personal choice. Current treatments, such as the loop electrosurgical excision procedure (LEEP), address lesions but do not eliminate persistent HPV infection and are associated with potential complications. Moreover, individuals treated for HPV-related disease are at increased risk for subsequent HPV-associated malignancies. These factors underscore an urgent need for effective, non-invasive therapeutic strategies capable of targeting and eradicating persistent HPV infections. Here we introduce NTX250, an innovative mRNA-based therapeutic platform designed to deliver HPV type 16 (HPV16) E6-E7 antigens, combined with immunomodulators human interleukin-12 (IL-12) p70 and engineered human LIGHT (LIGHT). The mRNAs are co-delivered via lipid and ionizable peptoid nanoparticles referred to as Nutshell formulation for intralesional administration. Our preclinical evaluation demonstrates that localized delivery of NTX250 in HPV16-transformed tumor-bearing models results in complete tumor regression and the induction of durable, antigen-specific immune memory. Moreover, this modular mRNA nanoparticle approach combining tumor-specific antigens and immunomodulators is adaptable beyond HPV, with potential applications targeting neoepitopes or other tumor-associated antigens, thus offering a versatile platform for immunotherapy across a broad range of indications. These findings highlight the potential of this strategy as a broadly applicable, non-surgical immunotherapeutic capable of inducing robust and specific anti-tumor responses.

immunology↗

bioRxiv2025

Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence

Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) evolution, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma (PXA), while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Longitudinal samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T-cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study opens new avenues for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.

cancer biology↗

bioRxiv2024

WAVE1 and WAVE2 facilitate human papillomavirus-driven actin polymerization during cellular entry

Human Papillomavirus Type 16 (HPV16) is an etiological agent of human cancers that requires endocytosis to initiate infection. HPV16 entry into epithelial cells occurs through a non-canonical endocytic pathway that is actin-driven, but it is not well understood how HPV16-cell surface interactions trigger actin reorganization in a way that facilitates entry. This study provides evidence that Wiskott-Aldrich syndrome protein family verprolin-homologous proteins 1 and 2 (WAVE1 and WAVE2) are molecular mediators of the actin polymerization that facilitates HPV endocytosis and intracellular trafficking. We demonstrate through post-transcriptional gene silencing and genome editing that WAVE1 and WAVE2 are critical for efficient HPV16 infection, and that restoration of each in knockout cells rescues HPV16 infection. Cells lacking WAVE1, WAVE2, or both, internalize HPV16 at a significantly reduced rate. Analysis of fluorescently labeled cells exposed to HPV16 and acquired by confocal fluorescence microscopy revealed that HPV16, WAVE1, WAVE2, and actin are all colocalized at the cellular dorsal surface. We also found that HPV16 stimulates WAVE1 and WAVE2-mediated cellular dorsal surface filopodia formation during the viral endocytic process. Taken together, this study provides evidence that the HPV endocytic process needed for infection is controlled by actin reorganization into filopodial protrusions and that this process is mediated by WAVE1 and WAVE2. Author SummaryHuman Papillomavirus (HPV) is the most common sexually transmitted infection in the United States. While its mode of entry into cells has yet to be fully described, extensive studies indicate HPV entry occurs via a macropinocytosis-like pathway. Interestingly, more than 10 viruses enter cells via macropinocytosis-like entry, with no two viruses utilizing identical factors for entry. It is unclear whether these viruses are entering cells via the same pathway, or if the term "macropinocytosis" describes a subset of endocytic pathways. One unifying feature of entry for each of these viruses is their requirement of actin polymerization. In this study, we identify the cellular factors necessary for actin polymerization to participate in HPV endocytosis. The findings of this study are of importance to the field of virology as they may extend to the infection of other viruses. It is also of interest in cancer studies as macropinocytosis has been associated with the scavenging of nutrients and methuosis, a form of cell death in cancer cells that occurs from over- scavenging. Nanoparticle delivery can also occur via macropinocytosis. Therefore, the contribution of WAVE proteins to macropinocytosis and macropinocytosis-like endocytic events is informative to a broad audience.

cell biology↗

bioRxiv2022

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors. Highlights- MHCII on intratumoral blood-borne myeloid cells is required for sustained anti-glioma T cell response - Loss of myeloid MHCII drives dysfunction of CD8+ T cells by activating TOX - Tox expression is induced by osteopontin-triggered chronic NFAT2 signaling in tumor-reactive CD8+ T cells - steopontin production is restricted upon intratumoral T helper cell activation via MHCII - MHCII expression on tumor-infiltrating bbm correlates with osteopontin expression and cytotoxic T cell dysfunction in human glioblastoma tissue O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/495502v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1fbedc7org.highwire.dtl.DTLVardef@b7dc3aorg.highwire.dtl.DTLVardef@db7fe6org.highwire.dtl.DTLVardef@aa06b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

NGS comparison of Downy and Powdery mildew resistance genomic regions between 'Regent' and 'Red Globe'

Powdery and downy mildew have a large negative impact on grape production worldwide. Quantitative trait loci (QTL) mapping projects have identified several loci for the genetic factors responsible for resistance to these pathogens. Several of these studies have focused on the cultivar Regent, which carries the resistance loci to downy mildew on chromosome 18 (Rpv3), as well powdery mildew on chromosome 15 (Ren3, Ren9). Several other minor resistance loci have also been identified on other chromosomes. Here we report on the re-sequencing of the Regent and Red Globe (susceptible) genomes using next generation sequencing. While the genome of Regent has more SNP variants than Red Globe, the distribution of these variants across the two genomes is not the same, nor is it uniform. The variation per gene shows that some genes have higher SNP density than others and that the number of SNPs for a given gene is not always the same for the two cultivars. In this study, we investigate the effectiveness of studying the variation of non-synonymous to synonymous SNP ratios between resistant and susceptible cultivars in the target QTL regions as a strategy to narrow down the number of likely candidate genes for Rpv3, Ren3 and Ren9.

genetics↗