Smart Self-Assembly Amphiphilic Cyclopeptide-Dye for Near-Infrared Window-II Imaging
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Chemistry↗
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Results for “Tumor microenvironment”
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Tumor microenvironment-activated self-recognizing nanodrug through directly tailored assembly of small-molecules for targeted synergistic chemotherapy
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Li, Yang (ORCID:0000000189501212)↗
NASA Smart Surgical Probe Project
Information Technologies being developed by NASA to assist astronaut-physician in responding to medical emergencies during long space flights are being employed for the improvement of women's health in the form of "smart surgical probe". This technology, initially developed for neurosurgery applications, not only has enormous potential for the diagnosis and treatment of breast cancer, but broad applicability to a wide range of medical challenges. For the breast cancer application, the smart surgical probe is being designed to "see" a suspicious lump, determine by its features if it is cancerous, and ultimately predict how the disease may progress. A revolutionary early breast cancer detection tool based on this technology has been developed by a commercial company and is being tested in human clinical trials at the University of California at Davis, School of Medicine. The smart surgical probe technology makes use of adaptive intelligent software (hybrid neural networks/fuzzy logic algorithms) with the most advanced physiologic sensors to provide real-time in vivo tissue characterization for the detection, diagnosis and treatment of tumors, including determination of tumor microenvironment and evaluation of tumor margins. The software solutions and tools from these medical applications will lead to the development of better real-time minimally-invasive smart surgical probes for emergency medical care and treatment of astronauts on long space flights.
Mah, Robert W.↗
Fibrotic activity quantified in serum by measurements of type III collagen pro-peptides can be used for prognosis across different solid tumor types
Due to activation of fibroblast into cancer-associated fibroblasts, there is often an increased deposition of extracellular matrix and fibrillar collagens, e.g. type III collagen, in the tumor microenvironment (TME) that leads to tumor fibrosis (desmoplasia). Tumor fibrosis is closely associated with treatment response and poor prognosis for patients with solid tumors. To assure that the best possible treatment option is provided for patients, there is medical need for identifying patients with high (or low) fibrotic activity in the TME. Measuring unique collagen fragments such as the pro-peptides released into the bloodstream during fibrillar collagen deposition in the TME can provide a non-invasive measure of the fibrotic activity. Based on data from 8 previously published cohorts, this review provides insight into the prognostic value of quantifying tumor fibrosis by measuring the pro-peptide of type III collagen in serum of a total of 1692 patients with different solid tumor types and discusses the importance of tumor fibrosis for understanding prognosis and for potentially guiding future drug development efforts that aim at overcoming the poor outcome associated with a fibrotic TME.
59 BASIC BIOLOGICAL SCIENCES↗
Patient-Specific Mathematical Model of the Clear Cell Renal Cell Carcinoma Microenvironment
The interactions between cells and molecules in the tumor microenvironment can give insight into the initiation and progression of tumors and their optimal treatment options. In this paper, we developed an ordinary differential equation (ODE) mathematical model of the interaction network of key players in the clear cell renal cell carcinoma (ccRCC) microenvironment. We then performed a global gradient-based sensitivity analysis to investigate the effects of the most sensitive parameters of the model on the number of cancer cells. The results indicate that parameters related to IL-6 have high a impact on cancer cell growth, such that decreasing the level of IL-6 can remarkably slow the tumor’s growth.
60 APPLIED LIFE SCIENCES↗
PI3Kαδ Inhibitor Combined With Radiation Enhances the Antitumor Immune Effect of Anti-PD1 in a Syngeneic Murine Triple-Negative Breast Cancer Model
The poor response of breast cancer to immune checkpoint blockade might result from low immunogenicity and the immune-suppressive tumor microenvironment. We hypothesized that in situ tumor vaccination via radiation therapy (RT) and suppression of immune tolerance via phosphoinositide 3-kinase δ (PI3Kδ) inhibition would enhance the efficacy of immune checkpoint blockade.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography
Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [ 89 Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (K a ) of 10 -8 M -1 and an immunoreactivity of 52%. Biodistribution studies in U87MG tumor-bearing mice revealed increasing radiotracer retention in tumors over time, leading to average tumor-to-muscle ratios of 3.1, 7.3, 7.2, and 8.3 at 2, 24, 48 and 72 h, respectively. Small animal PET corroborated the biodistribution studies; tumor-to-muscle ratios at 2, 24, 48, and 72 h were 2.0, 5.0, 6.1 and 7.8, respectively. Autoradiography demonstrated accumulated activity throughout the interior of FAP + tumors, while sequential tumor sections stained positively for FAP expression. Conversely, FAP - tissues retained minimal radioactivity and were negative for FAP expression by immunohistochemistry. These results demonstrate FAP as a promising biomarker that may be exploited to diagnose and potentially treat GBM and other neuroepithelial cancers.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Tumor Oxygenation by Myo-Inositol Trispyrophosphate Enhances Radiation Response
Tumor hypoxia is a major limiting factor for successful radiation therapy outcomes, with hypoxic cells being up to 3-fold more radiation resistant than normoxic cells; tumor hypoxia creates a tumor microenvironment that is hostile to immune response. Thus, pharmaceutical-induced tumor oxygenation before radiation therapy represents an interesting method to enhance the efficacy of radiation therapy. Myo-inositol trispyrophosphate (ITPP) triggers a decrease in the affinity of oxygen to hemoglobin, which leads to an increased release of oxygen upon tissue demand, including in hypoxic tumors.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
An activatable NIR fluorescent rosol for selectively imaging nitroreductase activity
Hypoxia (i.e., pO 2 ≤ ~1.5 %) is an important characteristic of tumor microenvironments that directly correlates with resistance against first-line therapies and tumor proliferation/infiltration. The ability to accurately identify hypoxic tumor cells/tissue could afford tailored therapeutic regimens for personalized treatment, the development of more-effective therapies, and discerning the mechanisms underlying disease progression. Fluorogenic constructs currently developed for identifying such tumor cells/tissue operate by targeting the bioreductive activity of primarily the nitroreductase (NTR) class of enzymes, but collectively such constructs unfortunately present photophysical and/or physicochemical shortcomings that could limit their effectiveness upon implementation. To overcome these limitations, we present the rational design, development, and evaluation of the first activatable ultracompact xanthene core-based molecular probe (NO 2 -Rosol) for selectively imaging NTR activity that affords an “OFF-ON” near-infrared (NIR) fluorescence response (ca. > 700 nm) alongside a remarkable Stokes shift (ca. > 150 nm) via NTR activity-facilitated modulation to its energetics whereby the resultant interplay discontinues an intramolecular d-PET fluorescence-quenching mechanism transpiring between directly-linked electronically-uncoupled π-systems comprising its components. DFT calculations guided selection of a suitable fluorogenic scaffold and nitroaromatic moiety candidate that when adjoined could (i) afford such photophysical response upon bioreduction by upregulated NTR activity in hypoxic tumor cells/tissue and (ii) employ a retention mechanism strategy that capitalizes on an inherent physical property of the NIR fluorogenic scaffold for achieving signal amplification. NO 2 -Rosol demonstrated 705 nm NIR fluorescence emission and a 157 nm Stokes shift, selectivity for NTR over relevant bioanalytes, and a 28- and 12-fold fluorescence enhancement in solution and between cells cultured under different oxic conditions, respectively. Finally, in establishing feasibility for NO 2 -Rosol to provide favorable contrast levels in in solutioand in vitrostudies, we anticipate NO 2 -Rosol similarly doing so in future studies towards its translation.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Novel CHI3L1 ‐Associated Angiogenic Phenotypes Define Glioma Microenvironments: Insights From Multi‐Omics Integration
ABSTRACT The CHI3L1 signaling pathway significantly influences glioma angiogenesis, but its role in the tumor microenvironment (TME) remains elusive. We propose a novelCHI3L1‐associated vascular phenotype classification for glioma through integrative analyses of multiple datasets with bulk and single‐cell transcriptome, genomics, digital pathology, and clinical data. We investigated the biological characteristics, genomic alterations, therapeutic vulnerabilities, and immune profiles within these phenotypes through a comprehensive multi‐omics approach. We constructed the vascular‐related risk (VR) score based onCHI3L1‐associated vascular signatures (CAVS) identified by machine learning algorithms. Utilizing unsupervised consensus clustering, gliomas were stratified into three distinct vascular phenotypes: Cluster A, marked by high vascularization and stromal activation with a relatively low levels of tumor‐infiltrating lymphocytes (TILs); Cluster B, characterized by moderate vascularization and stromal activity, coupled with a high density of TILs; and Cluster C, defined by low vascularization and sparse immune cell infiltration. We observed that the CAVS effectively indicated glioma‐associated angiogenesis and immune suppression by single‐cell RNA‐seq analysis. Moreover, the high‐VR‐score group exhibited enhanced angiogenic activity, reduced immune response, resistance to immunotherapy, and poorer clinical outcomes. The VR score independently predicted glioma prognosis and, combined with a nomogram, provided a robust clinical decision‐making tool. Potential drug prediction based on transcription factors for high‐risk patients was also performed. Our study reveals thatCHI3L1‐associated vascular phenotypes shape distinct immune landscapes in gliomas, offering insights for optimizing therapeutic strategies to improve patient outcomes.
Oncology↗
IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer
Due to lack of targetable receptors and intertumoral heterogeneity, triple negative breast cancer (TNBC) remains particularly difficult to treat. Doxorubicin (DOX) is typically used as nonselective neoadjuvant chemotherapy, but the diversity of treatment efficacy remains unclear. Comparable to variability in clinical response, an experimental model of TNBC using a 4T1 syngeneic mouse model was found to elicit a differential response to a seven-day treatment regimen of DOX. Single-cell RNA sequencing identified an increase in T cells in tumors that responded to DOX treatment compared to tumors that continued to grow uninhibited. Additionally, compared to resistant tumors, DOX sensitive tumors contained significantly more CD4 T helper cells (339%), γδ T cells (727%), Naïve T cells (278%), and activated CD8 T cells (130%). Furthermore, transcriptional profiles of tumor infiltrated T cells in DOX responsive tumors revealed decreased exhaustion, increased chemokine/cytokine expression, and increased activation and cytotoxic activity. γδ T cell derived IL-17A was identified to be highly abundant in the sensitive tumor microenvironment. IL-17A was also found to directly increase sensitivity of TNBC cells in combination with DOX treatment. In TNBC tumors sensitive to DOX, increased IL-17A levels lead to a direct effect on cancer cell responsiveness and chronic stimulation of tumor infiltrated T cells leading to improved chemotherapeutic efficacy. IL-17A’s role as a chemosensitive cytokine in TNBC may offer new opportunities for treating chemoresistant breast tumors and other cancer types.
4T1↗
Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy
T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.
60 APPLIED LIFE SCIENCES↗
Towards verifiable cancer digital twins: tissue level modeling protocol for precision medicine
Cancer exhibits substantial heterogeneity, manifesting as distinct morphological and molecular variations across tumors, which frequently undermines the efficacy of conventional oncological treatments. Developments in multiomics and sequencing technologies have paved the way for unraveling this heterogeneity. Nevertheless, the complexity of the data gathered from these methods cannot be fully interpreted through multimodal data analysis alone. Mathematical modeling plays a crucial role in delineating the underlying mechanisms to explain sources of heterogeneity using patient-specific data. Intra-tumoral diversity necessitates the development of precision oncology therapies utilizing multiphysics, multiscale mathematical models for cancer. This review discusses recent advancements in computational methodologies for precision oncology, highlighting the potential of cancer digital twins to enhance patient-specific decision-making in clinical settings. We review computational efforts in building patient-informed cellular and tissue-level models for cancer and propose a computational framework that utilizes agent-based modeling as an effective conduit to integrate cancer systems models that encode signaling at the cellular scale with digital twin models that predict tissue-level response in a tumor microenvironment customized to patient information. Furthermore, we discuss machine learning approaches to building surrogates for these complex mathematical models. These surrogates can potentially be used to conduct sensitivity analysis, verification, validation, and uncertainty quantification, which is especially important for tumor studies due to their dynamic nature.
60 APPLIED LIFE SCIENCES↗
Heterogeneous response of cancer-associated fibroblasts to the glucose deprivation through mitochondrial calcium uniporter
Highlights: • CAFs from a tumor mass are heterogeneous under the glucose deficient condition. • CAFs survive under glucose deficient condition by activation of TGF-β and calcium. • Calcium influx to mitochondria is critical for survival of glucose-deficient CAFs. • MCU in CAFs could be a feasible target for the development of anticancer drugs. Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have distinct features from normal fibroblasts (NFs). However, the discriminative nature of heterogeneous CAFs under glucose starvation remains unknown. In this study, we investigated the changes in the mitochondrial calcium concentration and relevant intracellular machinery in CAFs under glucose-deficient conditions. Xenografted tumor masses were dissected into multiple pieces and subjected to the CAF isolation using magnetically activated cell sorting (MACS). NFs were separated from the normal lung and skin. Under glucose starvation, CAFs from the tumor mass exhibited heterogeneity in cell proliferation, ATP production and calcium concentration. Compared to NFs, mitochondrial calcium concentration was significantly higher in glucose-starved CAFs with upregulation of mitochondrial calcium uniporter (MCU) that led to enhancement of ATP production and cell growth. Intriguingly, treatment of glucose-starved CAFs with oligomycin increased apoptosis by disrupted calcium homeostasis following overactivation of the mPTP. Moreover, oligomycin-induced apoptosis was mitigated by calcium chelation. This study demonstrated that the discriminative calcium influx to mitochondria through MCU coordinated cell growth and apoptosis in glucose-starved CAFs but not in NFs.
60 APPLIED LIFE SCIENCES↗
Electric Fields at Breast Cancer and Cancer Cell Collective Galvanotaxis
Cancer growth interferes with local ionic environments, membrane potentials, and transepithelial potentials, resulting in small electrical changes in the tumor microenvironment. Electrical fields (EFs) have significant effects on cancer cell migration (galvanotaxis/electrotaxis), however, their role as a regulator of cancer progression and metastasis is poorly understood. Here, we employed unique probe systems to characterize the electrical properties of cancer cells and their migratory ability under an EF. Subcutaneous tumors were established from a triple-negative murine breast cancer cell line (4T1), electric currents and potentials of tumors were measured using vibrating probe and glass microelectrodes, respectively. Steady outward and inward currents could be detected at different positions on the tumor surface and magnitudes of the electric currents on the tumor surface strongly correlated with tumor weights. Potential measurements also showed the non-homogeneous intratumor electric potentials. Cancer cell migration was then surveyed in the presence of EFs in vitro. Parental 4T1 cells and metastatic sublines in isolation showed random migration in EFs of physiological strength, whereas cells in monolayer migrated collectively to the anode. Our data contribute to an improved understanding of breast cancer metastasis, providing new evidence in support of an electrical mechanism that promotes this phenomenon.
59 BASIC BIOLOGICAL SCIENCES↗
Modeling immunity in microphysiological systems
There is a need for better predictive models of the human immune system to evaluate safety and efficacy of immunomodulatory drugs and biologics for successful product development and regulatory approvals. Current in vitro models, which are often tested in two-dimensional (2D) tissue culture polystyrene, and preclinical animal models fail to fully recapitulate the function and physiology of the human immune system. Microphysiological systems (MPSs) that can model key microenvironment cues of the human immune system, as well as of specific organs and tissues, may be able to recapitulate specific features of the in vivo inflammatory response. This minireview provides an overview of MPS for modeling lymphatic tissues, immunity at tissue interfaces, inflammatory diseases, and the inflammatory tumor microenvironment in vitro and ex vivo. Broadly, these systems have utility in modeling how certain immunotherapies function in vivo, how dysfunctional immune responses can propagate diseases, and how our immune system can combat pathogens.
Research & Experimental Medicine↗
National Cancer Institute Think-Tank Meeting Report on Proteomic Cartography and Biomarkers at the Single-Cell Level: Interrogation of Premalignant Lesions
A Think-Tank Meeting was convened by the National Cancer Institute (NCI) to solicit experts’ opinion on the development and application of multi-omic single-cell analyses, and especially single-cell proteomics, to improve the development of a new generation of biomarkers for cancer risk, early detection, diagnosis, prognosis as well as to discuss the discovery of new targets for prevention and therapy. It is anticipated that such markers and targets will be based on cellular, subcellular, molecular and functional aberrations within the lesion and within individual cells. Additionally, single-cell proteomic data will be essential for the establishment of new tools that with searchable and scalable features that include spatial and temporal cartographies of premalignant and malignant lesions. Challenges and potential solutions that were discussed included: • The best way/s to analyze single-cells from fresh and preserved tissue • Detection and analysis of secreted molecules and from single cells, especially from a tissue slice • Detection of new, previously undocumented cell type/s in the premalignant and early stage cancer tissue microenvironment • Multi-omic integration of data to support and inform proteomic measurements • Subcellular organelles – identifying abnormal structure, function, distribution and location within individual premalignant and malignant cells • How to improve the dynamic range of single-cell proteomic measurements for discovery of differentially expressed proteins and their post translational modifications (PTM) • The depth of coverage measured concurrently using single-cell techniques • Quantitation - absolute or semiquantitative? • Single methodology or multiplexed combinations? • Application of analytical methods for identification of biologically significant subsets • Data visualization of N-dimensional datasets • How to construct intercellular signaling networks in individual cells within premalignant tumor microenvironments (TME) • Associations between intrinsic cellular processes and extrinsic stimuli • How to predict cellular responses to stress inducing stimuli • Identification of new markers for prediction of progression from precursor, benign and localized lesions to invasive cancer, based on spatial and temporal changes within individual cells • Identification of new targets for immunoprevention or immunotherapy – identification of neoantigens and surfactome of individual cells within a lesion
59 BASIC BIOLOGICAL SCIENCES↗
Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles
Highlights: • ST-OMVs is a promising antitumor monotherapy or as an adjuvant to chemotherapies. • ST-OMVs downregulated Ki-67 and upregulated CD49b immune-expression. • ST-OMVs downregulated angiogenesis by inhibiting VEGF gene expression. • ST-OMVs increased tumor cells apoptosis and autophagy (increased caspase-3and Beclin1). Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.
60 APPLIED LIFE SCIENCES↗