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🦸♀️ #Breaking #Boundaries: Reprogrammed Tumour Cells Turn into Antigen-Presenting #Superheroes! 🦸♂️ Incredible scientific work by the Filipe Pereira lab and Asgard Therapeutics 💡 #Breakthrough: The research team utilised the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumour-APCs). This innovative approach involved enforced expression of PU.1, IRF8, and BATF3 (PIB), leading to the induction of the cDC1 phenotype in various cancer cell lines derived from both human and mouse haematological and solid tumours. 🌟 #Reprogramming the Immune System: The reprogramming process was a gradual and stepwise journey, ultimately resulting in tumour-APCs that acquired transcriptional and epigenetic programs associated with cDC1 cells. The newly created tumour-APCs exhibited enhanced antigen presentation and costimulatory molecules on their surfaces, effectively presenting endogenous tumour antigens on MHC-I. This breakthrough opened the door for targeted killing by CD8+ T cells, boosting the antitumor immune response. 🌐 #Broad Spectrum Success: The beauty of this approach lies in its broad applicability. The cDC1 reprogramming process was successfully applied to various cancer cell lines derived from different tissues and across species, proving its robustness and versatility. Moreover, patient-derived cancer cells and cancer-associated fibroblasts (CAFs) were also amenable to cDC1 reprogramming, demonstrating its potential to work with primary cancer cells from diverse origins. 🚀 #Clinical Implications: The implications of this research are profound. Tumour-APCs displayed decreased tumorigenicity in vitro and in vivo, providing a significant advantage over previous strategies that solely aimed to halt tumorigenesis. Furthermore, when injected into melanoma tumours, in vitro generated tumour-APCs significantly delayed tumour growth and improved survival in mice. The antitumor immunity elicited by these reprogrammed cells also showed synergy with immune checkpoint inhibitors, opening new avenues for combination therapies. 💼 #Translating the Findings: The authors envision the future clinical translation of their cancer reprogramming technology, which could be used to induce cDC1 fate and function in tumour cells in situ. This advancement could support immunotherapy in an adjuvant or neoadjuvant manner, bringing us one step closer to revolutionising cancer treatment. 🔬 #Moving Forward: Further research will focus on exploring non-integrative viral vectors, nonviral delivery methods, and cell-specific promoters for in vivo reprogramming, to ensure the safety and scalability of this cutting-edge cancer immunotherapy. The findings of this work represent a giant leap forward in cancer research, with the potential to transform the landscape of cancer treatment. #CancerResearch #Immunotherapy https://lnkd.in/e2XRXvdp

🧬Exploring Evolutionary Dynamics in Synthetic Systems 🧬 Are you curious about predicting the evolution of engineered cell populations? Exciting new research from Duncan Ingram and Guy-Bart Stan presents a groundbreaking framework that connects DNA design with mutation spread, shedding light on the dynamics of genetic stability. This innovative approach allows scientists to explore the optimisation of protein yield, genetic shelf life, and the design of gene regulatory networks. 🧬 Understanding the Challenge While models of evolutionary dynamics are not new, their application to synthetic systems has been limited due to the complex nature of genetic parts and regulatory elements. To bridge this gap, the researchers have developed a framework that connects DNA design to mutation dynamics in growing cell populations. 🧬The Framework The framework enables users to specify functional parts and mutation heterogeneity to explore. By generating host-aware transition dynamics, the model unveils how different mutation phenotypes evolve over time. It accounts for sequence-dependent mutation probabilities and gene expression-dependent growth rates, providing a comprehensive understanding of mutation dynamics. 🧬 Striking the Right Balance The framework introduces a part-driven approach to balance model complexity and usability. It allows researchers to explore the effects of mutating specific functional parts, such as promoters or RBS regions. By dissecting synthetic constructs into mutation states associated with distinct parts, the framework uncovers unique design considerations. 🧬 Beyond Genetic Parts The framework also considers gene expression dynamics, allowing researchers to explore variations in transcription and translation processes. While the current model focuses on transcription and translation elongation, future developments could incorporate additional components like the coding sequence, terminator, and origin of replication. This enhanced model could capture the effects of codon efficiency, termination efficiency, and copy number. 🧬Unlocking New Possibilities The framework's modularity enables its extension to various gene regulatory networks, uncovering evolutionary dynamics and providing insights into diverse synthetic devices. From feedforward loops to motifs within larger networks, the framework offers a powerful tool to analyse and optimise gene regulatory systems. This research opens up new horizons in biotechnology and synthetic biology, guiding researchers in designing more efficient and robust genetic constructs. The framework's potential to explore mutation dynamics and its impact on synthetic systems could revolutionise our understanding of engineered cell populations. #SyntheticBiology #GeneticEngineering #Biotechnology Article: https://lnkd.in/eeDqt2eU

🎯Antibody-based #TCR Fusion for Enhanced #TCell Cytotoxicity!💥 🔍The limitations of CAR-T therapy in solid tumour treatment have prompted researchers to explore novel strategies. This study introduces a synthetic T-cell receptor (TCR) platform that targets programmed death-ligand 1 (PD-L1), a molecule crucial in T-cell exhaustion within solid tumours. By fusing an antibody-based binding domain, known as a single-chain variable fragment (scFv), to the TCRγδ chains, they successfully enhanced T-cell cytotoxicity and anti-tumor response. 🎯 #Overcoming Major Challenges in Solid Tumour Treatment: Challenge 1: Identifying ideal tumour-specific targets and addressing tumour heterogeneity. Challenge 2: Overcoming physical barriers hindering T-cell infiltration into solid tumours. Challenge 3: Sustaining T-cell survival and function within the tumour microenvironment. 💡 #Integrating CAR-T and TCR-T Technologies The combination of CAR-T and PD-1/PD-L1 blockade has shown promise in solid tumour therapy. Expanding on this concept, the authors constructed a chimeric TCR that effectively targets PD-L1. The TCR platform fused the scFv derived from the anti-PD-L1 antibody Socazolimab to TCRγδ chains. TCRγδ was chosen for its strong proliferative response and the avoidance of potential mismatches with endogenous TCRβ chains. 🔬 #Promising Results: In vitro and in vivo experiments demonstrated the potent anti-tumor activities of the novel synthetic TCR. Both the γ-TCRγδ and δ-TCRγδ receptors effectively transduced signals, produced inflammatory cytokines, degranulated, and exerted tumour-killing activity upon engagement with PD-L1 antigen. Remarkably, γ-TCRγδ demonstrated superior efficacy over δ-TCRγδ in an in vivo xenograft model, suppressing tumour growth and exhibiting robust proliferative ability. 🌟#Implications for Future Immunotherapy: The scFv-TCRγδ design presents a new avenue for cancer immunotherapy, surpassing the capabilities of traditional CAR-T therapy. These findings highlight the potential of targeting the PD1/PD-L1 axis to treat solid tumours effectively. Further investigation is needed to explore the biological significance of the TCRδ chain within the synthetic TCRγδ heterodimer. To enhance safety, integrating a suicide gene into the construct can mitigate potential systemic toxicity. Excitingly, this study also validates the application of scFv-TCRγδ receptors for other antigen-specific targeting, exemplified by anti-CD19 scFv. 🚀 The development of this innovative scFv-γ-TCRγδ platform represents a leap forward in cancer immunotherapy. Thorough investigations and future studies are warranted to unlock the full potential of this novel approach. #Immunotherapy #CancerResearch #TCR #Tcell #CAR Article https://lnkd.in/eBxZXvuD