Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to harness immune cells: monoclonal ...antibodies against tumor antigens, immune checkpoint inhibitors, vaccination, adoptive cell therapies (e.g., CAR-T cells) and cytokine administration. In the last decades, it is emerging that the chemokine system represents a potential target for immunotherapy. Chemokines, a large family of cytokines with chemotactic activity, and their cognate receptors are expressed by both cancer and stromal cells. Their altered expression in malignancies dictates leukocyte recruitment and activation, angiogenesis, cancer cell proliferation, and metastasis in all the stages of the disease. Here, we review first attempts to inhibit the chemokine system in cancer as a monotherapy or in combination with canonical or immuno-mediated therapies. We also provide recent findings about the role in cancer of atypical chemokine receptors that could become future targets for immunotherapy.
Neutrophils in Gliomas Massara, Matteo; Persico, Pasquale; Bonavita, Ornella ...
Frontiers in immunology,
10/2017, Letnik:
8
Journal Article
Recenzirano
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Neutrophils are the most abundant white blood cells and are the first recruited to inflammatory sites. Neutrophils are an important component of the tumor stroma and can exert both anti-tumoral and ...pro-tumoral activities, depending on their maturation and activation state. In human gliomas, the number of circulating and infiltrating neutrophils correlates with the severity of the disease, indicating a prognostic and possible pro-tumoral role for these leukocytes. In glioma preclinical models, neutrophils promote tumor growth and orchestrate the resistance to anti-angiogenic therapies. Nevertheless, recent data indicate that neutrophils can be activated to directly kill tumor cells or to orchestrate the anti-tumoral response. Here, we review current knowledge about the role of neutrophils in glioma and their possible involvement in new strategies to improve current cancer therapies.
Highlights • Neutrophils are endowed with both pro- and antitumor functions. • Circulating neutrophils are a heterogeneous population. • Anti-tumoral (N1) neutrophils are present in early stages of ...tumors and metastasis while in later stages pro-tumoral (N2) neutrophils predominate. • CXC chemokines binding CXCR1 and CXCR2 are abundantly produced by tumors to recruit neutrophils. • After extravasation neutrophils acquire a new pattern of chemokine receptors including CCR2 that promote anti-tumoral activity.
Atypical chemokine receptors (ACKRs) are regulators of leukocyte traffic, inflammation, and immunity. ACKR2 is a scavenger for most inflammatory CC chemokines and is a negative regulator of ...inflammation. Here we report that ACKR2 is expressed in hematopoietic precursors and downregulated during myeloid differentiation. Genetic inactivation of ACKR2 results in increased levels of inflammatory chemokine receptors and release from the bone marrow of neutrophils with increased anti-metastatic activity. In a model of NeuT-driven primary mammary carcinogenesis ACKR2 deficiency is associated with increased primary tumor growth and protection against metastasis. ACKR2 deficiency results in neutrophil-mediated protection against metastasis in mice orthotopically transplanted with 4T1 mammary carcinoma and intravenously injected with B16F10 melanoma cell lines. Thus, ACKR2 is a key regulator (checkpoint) of mouse myeloid differentiation and function and its targeting unleashes the anti-metastatic activity of neutrophils in mice.
The tumor microenvironment plays a crucial role in determining response to treatment. This involves a series of interconnected changes in the cellular landscape, spatial organization, and ...extracellular matrix composition. However, assessing these alterations simultaneously is challenging from a spatial perspective, due to the limitations of current high-dimensional imaging techniques and the extent of intratumoral heterogeneity over large lesion areas. In this study, we introduce a spatial proteomic workflow termed Hyperplexed Immunofluorescence Imaging (HIFI) that overcomes these limitations. HIFI allows for the simultaneous analysis of > 45 markers in fragile tissue sections at high magnification, using a cost-effective high-throughput workflow. We integrate HIFI with machine learning feature detection, graph-based network analysis, and cluster-based neighborhood analysis to analyze the microenvironment response to radiation therapy in a preclinical model of glioblastoma, and compare this response to a mouse model of breast-to-brain metastasis. Here we show that glioblastomas undergo extensive spatial reorganization of immune cell populations and structural architecture in response to treatment, while brain metastases show no comparable reorganization. Our integrated spatial analyses reveal highly divergent responses to radiation therapy between brain tumor models, despite equivalent radiotherapy benefit.
The atypical chemokine receptor ACKR2 promotes resolution of acute inflammation by operating as a scavenger receptor for inflammatory CC chemokines in several experimental models of inflammatory ...disorders, however its role in the brain remains unclear. Based on our previous reports of increased expression of inflammatory chemokines and their corresponding receptors following traumatic brain injury (TBI), we hypothesised that ACKR2 modulates neuroinflammation following brain trauma and that its deletion exacerbates cellular inflammation and chemokine production. We demonstrate increased CCL2 and ACKR2 mRNA expression in post-mortem human brain, whereby ACKR2 mRNA levels correlated with later times post-TBI. This data is consistent with the transient upregulation of ACKR2 observed in mouse brain after closed head injury (CHI). As compared to WT animals, ACKR2-/- mice showed a higher mortality rate after CHI, while the neurological outcome in surviving mice was similar. At day 1 post-injury, ACKR2-/- mice displayed aggravated lesion volume and no differences in CCL2 expression and macrophage recruitment relative to WT mice. Reciprocal regulation of ACKR2 and CCL2 expression was explored in cultured astrocytes, which are recognized as the major source of CCL2 and also express ACKR2. ACKR2 mRNA increased as early as 2 hours after an inflammatory challenge in WT astrocytes. As expected, CCL2 expression also dramatically increased at 4 hours in WT astrocytes but was significantly lower in ACKR2-/- astrocytes, possibly indicating a co-regulation of CCL2 and ACKR2 in these cells. Conversely, in vivo, CCL2 mRNA/protein levels were increased similarly in ACKR2-/- and WT brains at 4 and 12 hours after CHI, in line with the lack of differences in cerebral macrophage recruitment and neurological recovery. In conclusion, ACKR2 is induced after TBI and has a significant impact on mortality and lesion development acutely following CHI, while its role in chemokine expression, macrophage activation, brain pathology, and neurological recovery at later time-points is minor. Concordant to evidence in multiple sclerosis experimental models, our data corroborate a distinct role for ACKR2 in cerebral inflammatory processes compared to its reported functions in peripheral tissues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brain metastases are the most common brain tumors in patients and are associated with poor prognosis. Investigating the colonization and outgrowth of brain metastases is challenging given the ...complexity of the organ, tissue sampling difficulty, and limited experimental models. To address this challenge, we employed a strategy to analyze the metastatic niche in established lesions, based on the release of a cell-penetrating mCherry tag from labeled tumor cells to neighboring niche cells, using different brain metastasis mouse models. We found that CD206+ macrophages were the most abundant cells taking up the mCherry label in established metastases. In vitro and in vivo experiments demonstrated that macrophages uptake and retain the canonical form of mCherry, even without the cell-penetrating portion of the tag. These results identify a specific macrophage subset in the brain that retains tumor-supplied fluorescent molecules, thereby complicating the long-term use of niche labeling strategies in established experimental brain metastasis.
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•The sLP-mCherry strategy detected host cells communicating with BrM tumor cells•CD206+ macrophages are associated with high uptake of sLP-mCherry•mCherry is taken up by CD206+ macrophages, even without the cell-penetrating tag
Microenvironment; Cell biology; Cancer
Review on divergent effects of ACKRs in the regulation of inflammation and immunity in cancer.
The chemokine system is a fundamental component of cancer‐related inflammation involved in all stages of ...cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC‐chemokine receptor 7, and atypical chemokine receptor 4/CC‐chemokine receptor‐like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC‐chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti‐inflammatory and immunotherapeutic strategies.
Con questa ricerca sono state individuate le Aree prioritarie per la conservazione della biodiversità della provincia di Novara quale operazione di partenza al fine di disegnare, in una fase ...successiva, la Rete Ecologica Provinciale su basi naturalistiche. A questa operazione hanno partecipato 26 naturalisti esperti, ossia dotati di competenze personali pregresse e di adeguata conoscenza del territorio della provincia di Novara, per i seguenti 6 temi focali: (a) Flora e vegetazione, (b) Invertebrati, (c) Anfibi e Rettili, (d) Uccelli, (e) Mammiferi, (f) Ecosistemi acquatici e pesci. Agli esperti è stato chiesto di individuare i temi focali più rappresentativi per la loro disciplina e di assegnare in modo comparativo un valore naturalistico di aree diverse del territorio provinciale. La metodologia adottata, basata sull’ottenimento delle informazioni dirette da parte dei maggiori esperti presenti sul territorio, è stata integrata per porzioni del territorio poco esplorato con un’analisi in ambiente GIS sulla base di database dell’uso del suolo e delle pressioni antropiche. Questo ha permesso di cartografare le aree più importanti per la conservazione della biodiversità. La gap analysis delle Aree prioritarie con le Aree protette e con altre categorie di tutela del territorio già presenti (parchi e riserve naturali, SIC, ZPS), ha permesso di valutare l’efficacia di queste seconde per la conservazione della biodiversità. Le Aree prioritarie sono state effettivamente localizzate quasi totalmente ma non esclusivamente in Aree protette. Tuttavia, l’insieme delle Aree protette del territorio novarese escludeva porzioni significative di territori di elevato valore per la biodiversità, ora meglio definiti con questa ricerca.
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