Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a ...pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that ...endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls anti-angiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer.
Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that ...tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization. We identify ECs as one of the major sources for interleukin-6 (IL-6) expression in GBM microenvironment. Furthermore, we reveal that colony-stimulating factor-1 and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor-γ-dependent transcriptional activation of hypoxia-inducible factor-2α. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors.
Cancer is one of the most important causes of human death. Early diagnosis and treatment can make patients live longer. Therefore, there is an urgent need to develop early and accurate diagnosis ...method for tumors. Molecular imaging technology can be used for qualitative and quantitative analyses at cellular and molecular levels, which provides a new technology for accurate diagnosis of tumors. In recent years, various nanomaterials with unique properties have been used for tumor molecular imaging. Meanwhile, aptamers are becoming an indispensable element in the design of functional nanomaterials because of their small size, high stability, and convenient modification, especially giving nanomaterials the ability to recognize specific targets. Therefore, aptamer-functionalized nanomaterials (AFNs) provide unprecedented opportunities for the field of tumor diagnosis. Here we focus on the latest development of AFNs in the molecular imaging of tumors. First, we introduce the characteristics and advantages of common aptamer-modified organic nanomaterials and inorganic nanomaterials. Then, the applications of AFNs in fluorescence imaging, computed tomography, magnetic resonance imaging, radionuclide imaging, ultrasound imaging, photoacoustic imaging, and multimode fusion imaging are discussed. Finally, we provide some perspectives on the challenges and opportunities that have arisen from this promising area.
Elaborated AFNs used in molecular imaging
Hepatocellular carcinoma (HCC) represents one of the deadliest cancers globally, making the search for more effective diagnostic and therapeutic approaches particularly crucial. ...Aptamer-functionalized nanomaterials (AFNs), an innovative nanotechnology, have paved new pathways for the targeted diagnosis and treatment of HCC. Initially, we outline the epidemiological background of HCC and the current therapeutic challenges. Subsequently, we explore in detail how AFNs enhance diagnostic and therapeutic efficiency and reduce side effects through the specific targeting of HCC cells and the optimization of drug delivery. Furthermore, we address the challenges faced by AFNs in clinical applications and future research directions, with a particular focus on enhancing their biocompatibility and assessing long-term effects. In summary, AFNs represent an avant-garde therapeutic approach, opening new avenues and possibilities for the diagnosis and treatment of HCC.
Cancer is a major cause of human death all over the world. Traditional cancer treatments include surgery, radiotherapy, chemotherapy, immunotherapy, and hormone therapy. Although these conventional ...treatment methods improve the overall survival rate, there are some problems, such as easy recurrence, poor treatment, and great side effects. Targeted therapy of tumors is a hot research topic at present. Nanomaterials are essential carriers of targeted drug delivery, and nucleic acid aptamers have become one of the most important targets for targeted tumor therapy because of their high stability, high affinity, and high selectivity. At present, aptamer-functionalized nanomaterials (AFNs), which combine the unique selective recognition characteristics of aptamers with the high-loading performance of nanomaterials, have been widely studied in the field of targeted tumor therapy. Based on the reported application of AFNs in the biomedical field, we introduce the characteristics of aptamer and nanomaterials, and the advantages of AFNs first. Then introduce the conventional treatment methods for glioma, oral cancer, lung cancer, breast cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, and prostate cancer, and the application of AFNs in targeted therapy of these tumors. Finally, we discuss the progress and challenges of AFNs in this field.
Tumor microenvironment (TME) is the cornerstone of the occurrence, development, invasion and diffusion of the malignant central nerve system (CNS) tumor, glioma. As the largest number of inflammatory ...cells in glioma TME, tumor associated macrophages (TAMs) and their secreted factors are indispensable to the progression of glioma, which is a well-known immunologically “cold” tumor, including the growth of tumor cells, invasion, migration, angiogenesis, cancer immunosuppression and metabolism. TAMs intimately interface with the treatment failure and poor prognosis of glioma patients, and their density increases with increasing glioma grade. Recently, great progress has been made in TAM-targeting for anti-tumor therapy. According to TAMs’ function in tumorigenesis and progression, the major anti-tumor treatment strategies targeting TAMs are to hinder macrophage recruitment in TME, reduce TAMs viability or remodel TAMs phenotype from M2 to M1. Different approaches offer unique and effective anti-tumor effect by regulating the phagocytosis, polarization and pro-tumor behaviors of macrophages in the therapy of glioma. The present review summarizes the significant characteristics and related mechanisms of TAMs and addresses the related research progress on targeting TAMs in glioma.
Anlotinib is a multi-target anti-angiogenic agent. This retrospective study aimed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide for the treatment of ...recurrent high-grade glioma.
The clinical data of patients with recurrent high-grade glioma treated with anlotinib alone or in combination with temozolomide in our cancer center were collected and analyzed. Treatment response was evaluated according to the response assessment for neuro-oncology criteria. Progression-free survival, progression-free survival at 6 months, overall survival, and overall survival at 12 months were evaluated by Kaplan-Meier method and compared by log-rank test.
Between August 2019 and December 2020, 31 patients with recurrent high-grade glioma (21 of grade 4 and 10 of grade 3) were enrolled in this study. Seventeen patients received anlotinib alone and 14 received anlotinib plus temozolomide. All patients were heavily treated, the median lines of previous treatments were 2, and the median Karnofsky score was 60. At the data cutoff date, the median progression-free survival was 4.5 months and the progression-free survival at 6 months was 43.5%. The median overall survival was 7.7 months, and the overall survival at 12 months was 26.7%. The progression-free survival at 6 months and the overall survival at 12 months for 21 patients with grade 4 glioma was 40.2 and 27.9%, respectively. The tumor objective response rate was 41.9% in all patients and 33.3% in patients with grade 4 glioma. No grade 3 or worse treatment-related adverse events were recorded during the treatment.
Anlotinib alone or in combination with temozolomide showed encouraging efficacy and favorable tolerability in patients with recurrent high-grade glioma who had been heavily treated.
Background
Surgical management for intracranial and extracranial communicating tumors is difficult due to the complex anatomical structures. Therefore, assisting methods are urgently needed. ...Accordingly, this study aimed to investigate the utility of a three-dimensional (3D)-printed model in the treatment of intracranial and extracranial communicating tumors as well as its applicability in surgical planning and resident education.
Methods
Individualized 3D-printed models were created for eight patients with intracranial and extracranial communicating tumors. Based on these 3D-printed models, a comprehensive surgical plan was made for each patient, after which the patients underwent surgery. The clinicopathological data of patients were collected and retrospectively analyzed to determine surgical outcomes. To examine the educational capability of the 3D-printed models, specialists and resident doctors were invited to review three of these cases and then rate the clinical utility of the models using a questionnaire.
Results
The 3D-printed models accurately replicated anatomical structures, including the tumor, surrounding structures, and the skull. Based on these models, customized surgical approaches, including the orbitozygomatic approach and transcervical approach, were designed for the patients. Although parameters such as operation time and blood loss varied among the patients, satisfactory surgical outcomes were achieved, with only one patient developing a postoperative complication. Regarding the educational applicability of the 3D-printed model, the mean agreement for all eight questionnaire items was above six (seven being complete agreement). Moreover, no significant difference was noted in the agreement scores between specialists and residents.
Conclusion
The results revealed that 3D-printed models have good structural accuracy and are potentially beneficial in developing surgical approaches and educating residents. Further research is needed to test the true applicability of these models in the treatment of intracranial and extracranial communicating tumors.
Radiotherapy and surgery are the standard local treatments for lung cancer brain metastases (BMs). However, limited studies focused on the effects of radiotherapy and surgery in lung cancer BMs with ...poor prognosis factors.
We retrospectively analyzed 714 patients with lung cancer BMs. Analyses of overall survival (OS) and risk factors for OS were assessed by the log-rank test and Cox proportional hazard model.
Age ≥ 65 years, a Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, and extracranial metastases were related to poor prognosis. Patients were stratified according to these poor prognosis factors. In patients with the ALK/EGFR wild type, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and surgery improved the OS of patients. WBRT and SRS were the independent protective factors for OS. In patients with extracranial metastases, patients who received WBRT plus SRS or WBRT alone had longer OS than those who did not receive radiotherapy. WBRT plus SRS and WBRT were the independent protective factors for OS.
Radiotherapy and surgery are associated with improved survival for lung cancer BMs with the ALK/EGFR wild type. Radiotherapy is associated with improved survival in lung cancer BMs with extracranial metastases.
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