Tumor-infiltrating myeloid cells convey proangiogenic programs that counteract the efficacy of antiangiogenic therapy. Here, we show that blocking angiopoietin-2 (ANG2), a TIE2 ligand and angiogenic ...factor expressed by activated endothelial cells (ECs), regresses the tumor vasculature and inhibits progression of late-stage, metastatic MMTV-PyMT mammary carcinomas and RIP1-Tag2 pancreatic insulinomas. ANG2 blockade did not inhibit recruitment of MRC1
+ TIE2-expressing macrophages (TEMs) but impeded their upregulation of
Tie2, association with blood vessels, and ability to restore angiogenesis in tumors. Conditional
Tie2 gene knockdown in TEMs was sufficient to decrease tumor angiogenesis. Our findings support a model wherein the ANG2-TIE2 axis mediates cell-to-cell interactions between TEMs and ECs that are important for tumor angiogenesis and can be targeted to induce effective antitumor responses.
► ANG2 blockade induces vascular regression in late-stage tumors ► ANG2 blockade inhibits growth and metastasis of late-stage tumors ► The ANG2/TIE2 axis regulates functional TEM association with angiogenic blood vessels ► Targeting the ANG2/TIE2 axis impedes evasive resistance to antiangiogenic therapy
Key Points
• The ICI score derived from gene expression profile of immune cells infiltrating GBM correlates with overall survival and is an effective prognostic biomarker.
• In this study, the ...authors developed a radiomics-based machine learning model able to identify gene expression profiles of GBM intratumoral stromal and immune cells and predict the ICI score on the preoperative MRI scans with high accuracy.
• Radiogenomics could potentially be applied in primary brain tumors to noninvasively assess the specific tumor immune characteristics, predict patients’ prognosis and identify those patients with higher probability to respond to immunotherapy.
Multidisciplinary management of patients with liver metastases (LM) requires a precision medicine approach, based on adequate profiling of tumor biology and robust biomarkers. Radiomics, defined as ...the high-throughput identification, analysis, and translational applications of radiological textural features, could fulfill this need. The present review aims to elucidate the contribution of radiomic analyses to the management of patients with LM. We performed a systematic review of the literature through the most relevant databases and web sources. English language original articles published before June 2020 and concerning radiomics of LM extracted from CT, MRI, or PET-CT were considered. Thirty-two papers were identified. Baseline higher entropy and lower homogeneity of LM were associated with better survival and higher chemotherapy response rates. A decrease in entropy and an increase in homogeneity after chemotherapy correlated with radiological tumor response. Entropy and homogeneity were also highly predictive of tumor regression grade. In comparison with RECIST criteria, radiomic features provided an earlier prediction of response to chemotherapy. Lastly, texture analyses could differentiate LM from other liver tumors. The commonest limitations of studies were small sample size, retrospective design, lack of validation datasets, and unavailability of univocal cut-off values of radiomic features. In conclusion, radiomics can potentially contribute to the precision medicine approach to patients with LM, but interdisciplinarity, standardization, and adequate software tools are needed to translate the anticipated potentialities into clinical practice.
Abstract
Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical ...imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.
A productive immune response requires transient upregulation of the microRNA miR-155 in hematopoietic cells mediating innate and adaptive immunity. In order to investigate miR-155 in the context of ...tumor-associated immune responses, we stably knocked down (KD) miR-155 in the myeloid compartment of MMTV-PyMT mice, a mouse model of spontaneous breast carcinogenesis that closely mimics tumor-host interactions seen in humans. Notably, miR-155/KD significantly accelerated tumor growth by impairing classic activation of tumor-associated macrophages (TAMs). This created an imbalance toward a protumoral microenvironment as evidenced by a lower proportion of CD11c+ TAMs, reduced expression of activation markers, and the skewing of immune cells within the tumor toward an macrophage type 2/T helper 2 response. This study highlights the importance of tumor-infiltrating hematopoietic cells in constraining carcinogenesis and establishes an antitumoral function of a prototypical oncomiR.
•miR-155 knockdown in myeloid cells accelerates spontaneous breast cancer development.•miR-155 is required by TAMs for deploying antitumoral activity.
Bone marrow-derived cells contribute to tumor angiogenesis. Here, we demonstrate that monocytes expressing the Tie2 receptor (Tie2-expressing monocytes TEMs) (1) are a distinct hematopoietic lineage ...of proangiogenic cells, (2) are selectively recruited to spontaneous and orthotopic tumors, (3) promote angiogenesis in a paracrine manner, and (4) account for most of the proangiogenic activity of myeloid cells in tumors. Remarkably, TEM knockout completely prevented human glioma neovascularization in the mouse brain and induced substantial tumor regression. Besides TEMs and endothelial cells (ECs), Tie2 expression distinguished a rare population of tumor stroma-derived mesenchymal progenitors representing a primary source of tumor pericytes. Therefore, Tie2 expression characterizes three distinct cell types required for tumor neovascularization: ECs, proangiogenic cells of hematopoietic origin, and pericyte precursors of mesenchymal origin.
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