Biology subjects

Ylä-Herttuala, S.

Publications and source records attributed to Ylä-Herttuala, S..

3 recordsLinked to original sources

bioRxiv2026

Multimodal immunopharmacologic screens identify drugs rewiring the cancer-immune interface

Natural killer (NK) cell-based therapies are a promising approach in cancer, but their efficacy is limited by impaired effector function and tumor-intrinsic resistance. To systematically identify therapeutic strategies that target both sides of the cancer-immune interface, we designed a multimodal immunopharmacologic screening platform comprising high-throughput co-culture drug screens, cytokine secretome profiling, single-cell perturbation screens, and genome-scale CRISPR screening, followed by validation in biobanked patient-derived models. Applying the platform across five blood cancer types, we identified protein kinase C (PKC) activation to simultaneously increase effector cytotoxicity and cytokine secretion through transcriptomic rewiring, and tumor susceptibility to NK cell killing through tumor-intrinsic PKC-{delta}. In patient samples, PKC activation sensitized NK-resistant leukemic progenitors to NK cell killing. In addition, NEDD8 inhibition enhanced NK function and shifted tumor TNF signaling towards pro-apoptotic pathways. Our platform provides a systematic approach to identify drugs rewiring both sides of the cancer-immune interface to circumvent tumor immune resistance.

cancer biology↗

bioRxiv2024

Automated and closed clinical-grade manufacturing protocol produces potent NK cells against neuroblastoma cells and AML blasts

Natural killer (NK) cells have great potential as allogeneic immune cell therapy due to their natural ability to recognize and kill tumor cells, and due to their apparent safety. This study describes the development of an immunotherapy option tailored for high-risk acute myeloid leukemia (AML) in adults and neuroblastoma in children. A GMP-compliant manufacturing protocol for the local production of functionally potent NK cells is detailed in the study, including a comprehensive description of the quality control strategy and considerations for product batch specifications in early clinical development. The protocol is based on the closed, automated CliniMACS Prodigy(R) platform (Miltenyi Biotec) and a modified Natural Killer Cell Transduction (NKCT) process without transduction and expansion. NK cells are isolated from leukapheresis through CD3 depletion and CD56 enrichment, followed by a 12-hour activation with cytokines (500 IU/ml IL-2, 140 IU/ml IL-15). Three CliniMACS Prodigy(R) NKCT processes were executed, demonstrating the feasibility and consistency of the modified NKCT process. A three-step process without expansion, however, compromised the NK cell yield. T cells were depleted effectively, indicating excellent safety of the product for allogeneic use. Phenotypic and functional characterization of the NK cells before and after cytokine activation revealed a notable increase in the expression of activation markers, particularly CD69, consistent with enhanced functionality. Intriguingly, even following a brief 12-hour activation period, the NK cells exhibited increased killing efficacy against CD33+ AML blasts isolated from patients and against SH-SY5Y neuroblastoma (NBL) target cells in vitro, suggesting a potential therapeutic benefit for AML and NBL patients.

immunology↗

bioRxiv2022

ErbB Signalling is a Potential Therapeutic Target for Vascular Lesions with Fibrous Component

BackgroundSporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to high recurrence of the lesions more effective therapies are needed. MethodsAs targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth. ResultsWe report, for the first time, expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of VEGF-A paracrinally, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts. ConclusionsBased on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component. FundingAcademy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Juselius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, and Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/509204v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@14ec94aorg.highwire.dtl.DTLVardef@1812747org.highwire.dtl.DTLVardef@39d01eorg.highwire.dtl.DTLVardef@18e9e35_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. Proposed model for the paracrine signaling of TGFA/VEGF-A in vascular lesion Schematic illustration showing the general structure of venous malformation or angiomatosis of soft tissue. Pathological vasculature in the lesion (dark blue) is surrounded by disorganized extracellular matrix (ECM) and intervascular stromal cells (SCs, orange). High magnification from the area close to vessel wall demonstrates the proposed model for crosstalk between endothelial cells (ECs) and SCs. A mutation in phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene (1) or other processes promote ECs to express high level of transforming growth factor A (TGFA) (2). TGFA binds to epithelial growth factor receptor (EGFR) on the surface of adjacent SCs (3). Activated EGFR-downstream signaling (4) promotes elevated expression of vascular endothelial growth factor (VEGF)-A in SCs and increases the expression of TGFA (5). VEGF-A secreted from SCs (6) binds to VEGF-recetor-2 (VEGFR2) on surface of ECs (7) and together with TGFA activates angiogenic EC phenotype. TGFA secreted from the SCs (8), can further activate EGFR and its downstream signaling. C_FIG

cell biology↗