Guevara, J. A. | bioRxiv Science

bioRxiv2024

Nanoparticles use magnetoelectricity to target and eradicate cancer cells

This study presents the first in vivo and in vitro evidence of an externally controlled, predictive, MRI-based nanotheranostic agent capable of cancer cell specific targeting and killing via irreversible electroporation (IRE) in solid tumors. The rectangular-prism-shaped magnetoelectric nanoparticle is a smart nanoparticle that produces a local electric field in response to an externally applied magnetic field. When externally activated, MENPs are preferentially attracted to the highly conductive cancer cell membranes, which occurs in cancer cells because of dysregulated ion flux across their membranes. In a pancreatic adenocarcinoma murine model, MENPs activated by external magnetic fields during magnetic resonance imaging (MRI) resulted in a mean three-fold tumor volume reduction (62.3% vs 188.7%; P < .001) from a single treatment. In a longitudinal confirmatory study, 35% of mice treated with activated MENPs achieved a durable complete response for 14 weeks after one treatment. The degree of tumor volume reduction correlated with a decrease in MRI T2* relaxation time (r = .351; P = .039) which suggests that MENPs have a potential to serve as a predictive nanotheranostic agent at time of treatment. There were no discernable toxicities associated with MENPs at any timepoint or on histopathological analysis of major organs. MENPs are a noninvasive alternative modality for the treatment of cancer. SummaryWe investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, [≥]300 {micro}g of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory studys experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

bioengineering↗

bioRxiv2024

Effector T Cells under Hypoxia have an Altered Transcriptome Similar to Tumor-Stressed T Cells Found in Non-Responsive Melanoma Patients

BackgroundIn the Tumor Microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma. MethodsTo generate detailed information on tumor oxygenation and T cell accessibility, we utilized mathematical modeling of human melanoma tissue microarrays (TMAs) that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors), ORIEN AVATAR (real-world melanoma patients treated with immune checkpoint inhibitors, ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes (TILs). ResultsWe made three specific observations: 1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 micrometers from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. 2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared to normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced Overall Survival (OS) and reduced progression-free survival (PFS) in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. 3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (TSTR). ConclusionOur study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and TSTR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs. Key MessagesWhat is already known on this topic: Hypoxia significantly impairs T cell functions, including reduced proliferation and cytokine production. This impairment may contribute to immune evasion and resistance to immune therapies, such as ICIs, adoptive transfer of TILs, and Chimeric Antigen Receptor (CAR) T cells. Despite the established impact of hypoxia on T cell function, the precise spatial distribution of T cells in relation to oxygen availability within the TME and how this affects clinical outcomes in melanoma patients remains unclear. Additionally, the specific transcriptional changes in T cells induced by hypoxia and their prevalence in different T cell states, as well as the implications for resistance to ICIs, have not been thoroughly investigated. Understanding these aspects is crucial for developing targeted therapies to overcome hypoxia-induced resistance and improve immunotherapy efficacy. What this study adds: This study elucidates the profound impact of hypoxia on T cells in melanoma. Our findings reveal that T cells accumulate in well-oxygenated regions near blood vessels, whereas hypoxic conditions significantly impair their proliferation and cytokine production. By addressing the transcriptional changes induced by hypoxia, we demonstrated its prevalence in resting and non-activated T cells and TSTR. Moreover, we found that hypoxia is associated with shorter OS and PFS in melanoma patients, particularly in non-responders to ICIs. This research highlights the critical role of hypoxia in modulating T cell spatial behavior, contributing to immune evasion and poor clinical outcomes in melanoma. How this study might affect research, practice, or policy: The findings emphasizes hypoxias critical role in modulating T cell behavior and its potential as a biomarker for treatment outcomes. These insights could inform the development of therapeutic strategies aimed at improving T cell function in hypoxic TMEs, thereby enhancing the efficacy of immunotherapies for melanoma and other solid tumors. Additionally, the studys results may influence policies regarding the evaluation and implementation of combination therapies that target hypoxia to improve patient outcomes.

immunology↗