Immunogenic Cell Death Inducers in Cancer Immunotherapy to Turn Cold Tumors into Hot Tumors

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1613 - 1613

Published: Feb. 14, 2025

The combination of chemotherapeutic agents with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. However, its success is often limited by insufficient priming in certain tumors, including pediatric malignancies. In this report, we explore clinical trials currently investigating the use immunogenic cell death (ICD)-inducing chemotherapies ICIs for both adult and cancers. Given data available focused on recent preclinical studies evaluating efficacy these combinations neuroblastoma (NB). Finally, to address gap, propose an innovative strategy assess impact ICD-inducing antitumor responses NB. Using tumor spheroids derived from a transgenic NB mouse model, validated our previous vivo findings concerning how anthracyclines, specifically mitoxantrone doxorubicin, significantly enhance MHC class I surface expression, stimulate IFNγ granzyme B production CD8+ T cells NK cells, promote recruitment. Importantly, anthracyclines also upregulated PD-L1 expression spheroids. This screening platform yielded results similar findings, demonstrating that doxorubicin are most potent immunomodulatory These suggest creation libraries ICD inducers be tested could reduce number vivo, line principles 3Rs. Furthermore, highlight potential chemo-immunotherapy regimens counteract immunosuppressive microenvironment NB, paving way improved therapeutic strategies They provide compelling evidence support further investigations outcomes children

Language: Английский

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Phase I study of safety and efficacy of allogeneic natural killer cell therapy in relapsed/refractory neuroblastomas post autologous hematopoietic stem cell transplantation

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 9, 2024

Language: Английский

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The anti-GD2 monoclonal antibody naxitamab plus GM-CSF for relapsed or refractory high-risk neuroblastoma: a phase 2 clinical trial

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 14, 2025

Abstract In this single-arm, non-randomized, phase 2 trial (NCT03363373), 74 patients with relapsed/refractory high-risk neuroblastoma and residual disease in bone/bone marrow (BM) received naxitamab on Days 1, 3, 5 (3 mg/kg/day) granulocyte-macrophage colony-stimulating factor (Days -4 to 5) every 4 weeks, until complete response (CR) or partial (PR) followed by additional cycles weeks. Primary endpoint the prespecified interim analysis was overall (2017 International Neuroblastoma Response Criteria). Among 26 responders (CR + PR) efficacy population ( N = 52), 58% had refractory disease, 42% relapsed disease. Overall rate (ORR) 50% (95% CI: 36-64%), CR PR were observed 38% 12%, respectively. With 95% CI lower limit for ORR exceeding 20%, primary of met. Patients evaluable bone a (29/50) compartment (CR, 40%; PR, 18%). BM 74% (17/23; CR, 74%). One-year survival progression-free (secondary endpoints) 93% 80-98%) 35% 16-54%), Naxitamab-related Grade 3 adverse events included hypotension (58%) pain (54%). Overall, demonstrated clinically meaningful manageable safety bone/BM.

Language: Английский

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PHD-2/HIF-1α axis mediates doxorubicin-induced angiogenesis in SH-SY5Y neuroblastoma microenvironment: a potential survival mechanism

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 3, 2025

Abstract The response of neuroblastoma (NB) cells to chemotherapeutics and their influence on NB microenvironment remain incompletely understood. Herein, we examined the underlying molecular mechanism via which Doxorubicin, a chemotherapeutic agent used for treatment, promotes proangiogenic in SH-SY5Y microenvironment. Doxorubicin treatment at 1 µg/ml reduced cell proliferation primed apoptosis pathway. Unexpectedly, treated with doxorubicin upregulated expression pro-angiogenic factors, including vascular endothelial growth factor (VEGF), platelets-derived (PDGF), matrix metalloprotease-2 (MMP-2) secretion nitric oxide. To assess functional angiogenesis pre-treated doxorubicin, an indirect co-culture system human umbilical vein (HUVEC) was established. These HUVECs acquired enhanced proliferation, migration capacity, tube formation capability exhibited increased oxide (NO) production, addition α-smooth muscle actin expression, suggesting contractility. In-ovo studies neo-angiogenic further show promoted neo-angiogenesis as indicated by generated blood vessels histological analysis CD31 expression. Inhibition PHD-2 could be potential target docking, dynamics (MD) simulation, MM-GBSA calculations, leading hypoxia-inducible factor-1 alpha (HIF-1α) stabilization. Bioinformatics analyses enrichment RNA-seq data revealed activation Pi3K pathway is validated in-vitro. results provide evidence unexpected suggest use multi-modal therapeutic regimens more comprehensive approach treatment.

Language: Английский

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Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Abstract High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA ATAC sequencing whole-genome sequencing. This revealed profound shifts in immune cell subpopulations therapy identified enhancer-driven transcriptional regulators neoplastic states. Poor outcome correlated proliferative metabolically active states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions mesenchymal cells increased high proportion poorer response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive metabolic phenotypes. We paracrine signaling networks validated the HB-EGF–ERBB4 axis between macrophage subsets, which promoted growth through ERK signaling. These findings collectively reveal intrinsic extrinsic response neuroblastoma.

Language: Английский

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Hallmarks of Neuroblastoma—Pathophysiology, Diagnosis, and Therapeutic Interventions

Published: May 19, 2025

ABSTRACT Neuroblastoma, the most common extracranial solid tumor in childhood, continues to challenge clinicians and researchers because of its heterogeneous nature complex pathophysiology. Recent breakthroughs molecular profiling revealed intricate genetic alterations driving progression, necessitating an updated perspective on disease’s Rapid advancements diagnostic techniques, including novel imaging modalities assays, warrant a thorough examination guide clinical decision‐making. Furthermore, emergence targeted therapies immunotherapeutic approaches dramatically shifted treatment landscape, creating urgent need for critical evaluation their efficacy integration into existing protocols. This comprehensive review is critically needed synthesize latest understanding hallmarks neuroblastoma, evolving therapeutic approaches. By consolidating current knowledge identifying gaps, this aims provide valuable resource researchers, potentially catalyzing new research directions improving patient outcomes.

Language: Английский

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Targeting Pathways in Neuroblastoma: Advances in Treatment Strategies and Clinical Outcomes

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(10), P. 4722 - 4722

Published: May 15, 2025

Neuroblastoma (NB) is a childhood cancer originating from neural crest cells of the sympathetic nervous system. Despite advances in multimodal therapy, treatment high-risk NB remains challenging. The present review outlines several evidence-related insights into molecular mechanisms pathogenesis, focusing on genetic drivers (e.g., MYCN amplification) and disrupted signaling pathways (PI3K/Akt/mTOR; Notch; Jak2/STAT3), as well tumor microenvironment’s role progression resistance. authors highlight current emerging therapeutic strategies, including molecularly targeted agents; immunotherapies; differentiation approaches under investigation. complexity heterogeneity underscores need for continued translational research combined strategies aimed at improving outcomes affected children, highlighting integration profiling precision medicine to guide treatment.

Language: Английский

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Exploring the Role of Fibroblasts in Promoting Neuroblastoma Cell Migration and Invasion

Journal of Nanotheranostics, Journal Year: 2024, Volume and Issue: 5(4), P. 212 - 227

Published: Dec. 8, 2024

Neuroblastoma, the most common pediatric extracranial solid tumor, arises from malignant transformation of neural crest progenitors in peripheral nervous system. Its clinical and genetic heterogeneity poses significant challenges, especially high-risk patients with metastatic disease. Two plastic neuroblastoma cell phenotypes, adrenergic (ADR) mesenchymal (MES), have been identified. Notably, MES cells exhibit increased migration chemoresistance. Cancer-associated fibroblasts (CAFs) tumor microenvironment further promote aggressiveness by enhancing cancer proliferation, extracellular matrix remodeling, angiogenesis metastasis. This study explored role non-activated ADR invasion vitro vivo. Results showed that influenced fibroblast activation into CAFs differently, promoting a more invasive environment leading to spread. These findings enhance our understanding how phenotypes contribute formation pro-metastatic niche activating CAFs. insight could inform new therapeutic strategies targeting prevent

Language: Английский

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