In vitro models to mimic tumor endothelial cell-mediated immune cell reprogramming in lung adenocarcinoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract Tumor endothelial (TECs) cells play a critical role in regulating immune responses within the tumor microenvironment (TME). However, mechanisms by which TECs modulate cell population remain unclear, particularly non-small lung cancer (NSCLC). Here, we investigated how NSCLC tweak normal (NECs) into and subsequent effects on regulation. NECs were cocultured with various lines, using 2D 3D coculture models to evaluate TEC-mediated cells. We show that direct led significant transcriptomic, proteomic kinomic alterations TECs, especially pro-inflammatory pathways. identified downregulation of co-stimulatory molecule OX40L compared NECs, suggesting impaired T-cell proliferation support. While showed limited effect CD8+ activation, supported CD4 T-cells polarization Treg Th22 subsets. Moreover, also promoted M2-like macrophages polarization, thereby potentially contributing TME immunosuppression. State-of-the-art single-cell RNA sequencing multicellular spheroids (MCTS) revealed distinct TEC subpopulations, including an inflammatory subset UPR signature. The latter was absent 2D-cultured but present freshly isolated from patients. Importantly, MCTS perivascular macrophage subset, predicted interact MIF Midkine signaling. In conclusion, tumors pivotal remodeling landscape promoting suppression. This study highlights complex immunoregulatory functions our different vitro mimic aspects TME. Our data may provide new insights potential therapeutic strategies targeting or regulatory signaling improve efficacy immunotherapy NSCLC.

Language: Английский

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Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 9853 - 9853

Published: Sept. 12, 2024

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining homeostasis by controlling the passage substances and cells. In tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives angiogenesis, leading to anergy immunosuppression—a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness significantly reduced EC anergy. Anti-angiogenic treatments aim normalize vessels improve infiltration. Despite potential, these therapies often cause significant systemic toxicities, necessitating new treatments. small GTPase Rap1B emerges as critical regulator Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific knockout mice show that absence impairs growth, alters vessel morphology, increases infiltration activation. This indicates mediates VEGF-A’s immunosuppressive effects, making it promising target overcoming immunosuppression cancer. shares structural functional similarities with RAS oncogenes. We propose targeting could enhance therapies’ efficacy while minimizing adverse effects reversing briefly discuss strategies successfully developed model developing anti-Rap1 therapies.

Language: Английский

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Inhibiting autophagy selectively prunes dysfunctional tumor vessels and optimizes the tumor immune microenvironment

Theranostics, Journal Year: 2024, Volume and Issue: 15(1), P. 258 - 276

Published: Dec. 2, 2024

Dysfunctional tumor vasculature, hypoxia, and an immunosuppressive microenvironment are significant barriers to effective cancer therapy. Autophagy, which is critical for maintaining cellular homeostasis apoptosis resistance, primarily triggered by hypoxia nutrient deprivation, conditions prevalent in dysfunctional vessels due poor circulation. However, the role of autophagy endothelial cells its impact on treatment (TME) remain poorly understood. Methods: We used multiplex immunofluorescence transgene-based imaging characterize from clinical samples, zebrafish xenograft tumors, murine models. Using a vasculature platform, we analyzed effects inhibitors structure function vasculature. In mice, investigated inhibition via endothelial-specific gene knockout (Atg7 iECKO) inhibitor SBI-0206965 evaluated synergistic combining with low-dose chemotherapy (5-fluorouracil, 5-FU) or PD-1 antibody. Human umbilical vein (HUVECs) were cultured vitro under hypoxic, glucose-deprived, serum-free simulate explore mechanisms optimizes Results: Elevated was observed within Autophagy inhibition, through either genetic pharmacological selectively prunes improves vascular function. It also stimulates formation perivascular immune niche, thereby optimizing (TiME). Furthermore, 5-FU antibody potentiated anti-tumor effects. Mechanistic studies have indicated that acts as protective response hypoxic nutrient-deprived TME, while mediated p53 activation, promotes cell vessels, further Conclusions: Targeting promising strategy remodeling TiME, boosting efficacy immunotherapy.

Language: Английский

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Endothelial autophagy blockade fosters anti-cancer immunity

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 16(1), P. 1 - 3

Published: Dec. 20, 2023

The discovery of immune checkpoints, consisting transmembrane ligand-receptor protein pairs that negatively regulate the CD8+ T-cell-mediated response by antigen-presenting cells (APCs) and cancer cells, has enabled a fundamental advancement therapies (Korman et al, 2022). Indeed, harnessing these homeostatic control mechanisms to their own advantage, tumor manage defend themselves from attack system, checkpoint blockade (ICB) proven be an overwhelmingly successful antitumor therapeutic approach

Language: Английский

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