Biology subjects

Peine, S.

Publications and source records attributed to Peine, S..

5 recordsLinked to original sources

bioRxiv2024

Accessing the specific capacity of TIL-derived CD8 T-cells to suppress tumor recurrence in resectable HBV-HCC patients

BackgroundHepatocellular carcinoma represents a significant global health challenge, affecting over a million patients annually, arising mainly from chronic liver diseases, with a majority being related to viral infections. However, despite the groundbreaking clinical results of immune checkpoint blockades and adoptive cell therapies, we still face non-responders accompanied by high rebound rates after resection. Considering that the main concern is to overcome a highly specialized immunosuppressive tumor microenvironment of the individual patient, the characterization of the particular tumor microenvironment and the source of the immune cells used in ACT is of immense importance. Approved ACT therapies mainly use modified peripheral blood cells from individuals. At the same time, tumor-infiltrating lymphocytes are underrepresented even if they have garnered interest due to their potential to target tumor-specific antigens more effectively. MethodsIn this study, we employed allogenic and autologous immune cell sources for expansion and stimulation, resulting in adoptive T-cell transfer experiments determining the effector cell differentiation and the related anti-tumor effects by the possible implementation of re-stimulation. ResultsWe determined a high success rate in expanding and stimulating tumor-infiltrating lymphocytes with consistent CD8 T-cell fractions from HCC patients. To showcase the effectiveness of stimulated T-cells from different sources, we generated cell lines derived from the margin and center of an HBV-induced HCC with a highly immune-suppressive TME. We found effective immune responses supported by cell death induction, ferroptosis, proptosis and apoptosis triggered by all sources of T-cells depending on the area of derived tumor cells. ConclusionEffector T-cell fractions derived from tumor-infiltrating lymphocytes present a viable source for cell-based immune therapy combined with immune checkpoint inhibitors in HCC patients, especially after resection, to suppress rebound strategies of the parental tumor on an individual level.

immunology↗

bioRxiv2024

Patient-derived HCC cells recapitulating the transcriptomic landscape of primary HCV-related liver cancer

BackgroundThe hepatocellular carcinoma is one of the leading causes of cancer-related mortality and is characterized by high heterogeneity and subsequently adaptation by developing resistance to current treatments. In this scenario the application of individualized models is crucial to understand the potential of approved therapies. Recently, we established a series of individual cell lines derived from patients who developed HCC on different entities, serving as a platform for individual approaches. In this study, we classified the LC4 cells derived from the center region of a HCC with underlying HIV-HCV co-infection, by using deep analysis on the pathway regulation level. MethodsWe employed DEG analysis, followed by pathway analysis to characterize the preservation level of the LC4 cells and the level of adoption. Next, we classify the model, by employing healthy donor samples, commonly used HCC cell lines and global RNAseq data sets. ResultsWe showed that the LC4 cells reflect significant characteristics of the parental region, including the replication of the immuno-suppressive and the proliferative milieu. The LC4 cells exhibit a metabolic reprogramming characterized by the downregulation of drug-metabolizing CYP enzymes compared to healthy individuals, indicating a transition to alternate metabolic pathways. Moreover, we identified common Biomarkers in the parental tissue, global datasets and the LC4 cells. ConclusionWe showed that the LC4 cell line is applicable as an individual model for pre-clinical testing of treatment regimens in HCC driven research.

cancer biology↗

bioRxiv2024

Red blood cell-tumour cell interactions promote tumour cell progression

One critical step in the metastatic cascade is the survival of circulating tumour cells (CTCs) within the bloodstream. While numerous interactions between CTCs and various hematopoietic cells have been described, the role of red blood cells (RBCs) in this process remains underexplored. This study investigates the interactions between tumour cells and RBCs from breast and lung cancer patients, revealing significant phenotypic and functional changes in the tumour cells, unlike when the contact is with RBCs from healthy donors. In vitro co-culture of cancer cell lines with RBCs from metastatic cancer patients resulted in increased tumour cell attachment accompanied by morphological changes. Additionally, RBCs-primed tumour cells showed increased adhesion and disruption of the endothelial barrier in vitro and increased invasiveness both in vitro and in vivo. Transcriptomic analysis showed that RBCs from metastatic breast cancer patients induce significant gene expression changes, notably upregulating PAK4, which enhances migration and epithelial-mesenchymal transition. PAK4 inhibition reduced these effects. Proteomic studies revealed substantial remodelling, including actin-related changes and the accumulation of VASP at cell edges, promoting directional migration. Clinically, higher RBC distribution width (RDW) in metastatic breast cancer patients is associated with increased CTC counts and worse outcome. This study highlights the previously unrecognized role of RBCs in promoting metastatic behaviours in cancer cells and suggests potential therapeutic targets, such as PAK4, to counteract these effects. Further exploration of RBCs-tumour cell interactions could provide new insights into metastatic mechanisms and improve cancer prognosis and treatment strategies. Key PointsO_LIThis study reveals the previously unknown role of RBCs in enhancing tumour cell invasiveness and metastatic potential. C_LIO_LITumour cells undergo significant phenotypic and functional changes after contact with RBCs from cancer patients. C_LI

cancer biology↗

bioRxiv2024

Iron transport pathways in the human malaria parasite Plasmodium falciparum revealed by RNA-sequencing

Host iron deficiency is protective against severe malaria as the human malaria parasite Plasmodium falciparum depends on bioavailable iron from its host to proliferate. The essential pathways of iron acquisition, storage, export, and detoxification in the parasite differ from those in humans, as orthologs of the mammalian transferrin receptor, ferritin, or ferroportin, and a functional heme oxygenase are absent in P. falciparum. Thus, the proteins involved in these processes may be excellent targets for therapeutic development, yet remain largely unknown. Here, we show that parasites cultured in erythrocytes from an iron-deficient donor displayed significantly reduced growth rates compared to those grown in red blood cells from healthy controls. Sequencing of parasite RNA revealed diminished expression of genes involved in overall metabolism, hemoglobin digestion, and metabolite transport under low-iron versus control conditions. Supplementation with hepcidin, a specific ferroportin inhibitor, resulted in increased labile iron levels in erythrocytes, enhanced parasite replication, and transcriptional upregulation of genes responsible for merozoite motility and host cell invasion. Through endogenous GFP tagging of differentially expressed putative transporter genes followed by confocal live-cell imaging, proliferation assays with knockout and knockdown lines, and protein structure predictions, we identified six proteins that are likely required for ferrous iron transport in P. falciparum. Of these, we localized PfVIT and PfZIPCO to cytoplasmic vesicles, PfMRS3 to the mitochondrion, and the novel putative iron transporter PfE140 to the plasma membrane for the first time in P. falciparum. PfNRAMP/PfDMT1 and PfCRT were previously reported to efflux Fe2+ from the digestive vacuole. Our data support a new model for parasite iron homeostasis, in which PfE140 is involved in iron uptake across the plasma membrane, PfMRS3 ensures non-redundant Fe2+ supply to the mitochondrion as the main site of iron utilization, PfVIT transports excess iron into cytoplasmic vesicles, and PfZIPCO exports Fe2+ from these organelles in case of iron scarcity. These results provide new insights into the parasites response to differential iron availability in its environment and into the mechanisms of iron transport in P. falciparum as promising candidate targets for future antimalarial drugs.

cell biology↗

bioRxiv2024

NSCLC patients with oligo-metastatic brain disease show an altered CD4 T-cells immune profile

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide, with brain metastasis (BM) occurring in 40% of advanced non-small cell lung cancer (NSCLC) patients. In 15% of these patients, the brain is the only affected organ (oligo-metastasis), corresponding to improved prognosis compared to widespread disease. Thus far, it is unknown if the metastatic dissemination to the brain without systemic metastases is a consequence of the immune systems ability to control systemic tumor outgrowth. MethodsHere, we investigated the local and peripheral immune cell composition in NSCLC BM patients, and identified new immune patterns related to the occurrence of brain metastases either as oligo- or poly-metastatic disease. ResultsThe multi-parametric immune phenotyping of peripheral blood revealed a downregulation of KLRG1 in CD8+ T-cells and an increase in CD4+ TH17 cells and elevated IL-17 levels in the blood of all NSCLC BM patients compared to healthy individuals. In addition, BM patients CD4+ T cells showed less CD73 expression with reduced effector memory differentiation. Furthermore, we observed less intra-tumoral infiltration in tumor tissues and a distinctive CD4+ T-cell profile in oligo-synchronous BM, both in the tumor microenvironment and peripheral blood compared to poly-metastatic BM patients. Moreover, 5'-ectonucleotidase CD73 was significantly upregulated in CD4 and T-regulatory cells of oligo-synchronous BM. ConclusionsThese results indicate that oligo-synchronous BM exhibits a more pronounced alteration in the CD4 T-cell immune profile both locally at the tumor site and systemically. Key PointsO_LIBM patients exhibit a skewed systemic immune profile, characterized by downregulation of KLRG1 in CD8+ and induction of TH17/IL-17 axis and CD73 in CD4+ T-cells. C_LIO_LIOligo-synchronous BM displayed a distinct CD4+ T-cell profile in both TME and peripheral blood. C_LI Importance of the StudyThis study presents a novel insight into immune profiles of brain metastasis types in NSCLC patients. Examining tissues and PBMCs sheds light on the disease and uncovers unique immune responses within distinct brain metastasis patterns. This research offers valuable knowledge for improved understanding and identifying potential prognosis markers.

cancer biology↗