Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies ...have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47-signal-regulatory protein α (SIRPα) axis, either alone or in combination with other cancer therapies. In this Review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the effect of phagocytosis checkpoint blockade on induction of antitumour immune responses. Given the role of innate immune cells in priming adaptive immune responses, an improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.
East Asia is characterized by an east-west topographic dichotomy on the two sides of the North-South Gravity Lineament (NSGL), a feature not associated with major basement boundaries. The NSGL also ...marks an abrupt change in the thickness of the continental crust and the lithospheric mantle, as well as that in the associated residual topography. Both the mechanism and timing for the formation of this unique East Asian lithospheric property remain unclear. We reviewed the key tectonic records of East Asia since the early Mesozoic, with a particular focus on the plausible underlying mantle dynamics. The observation that widespread Jurassic-Early Cretaceous crustal extension occurred on both sides of the NSGL and that Cenozoic rift basins were predominantly to the east of the NSGL suggests that the seismically observed East Asian lithospheric structure came into being no earlier than the Cretaceous. Several flat-slab models have been proposed. We suggest that a combination of these models could explain the unique East Asian lithospheric evolution since the Middle Mesozoic. Further ground truth using quantitative geodynamic models with data assimilation demonstrates that a flat slab could significantly reduce the thickness of the overriding plate by dislocating and entraining the lower mantle lithosphere. Meanwhile, an advancing flat slab causes widespread upper-lithosphere compression and disappearance of the mantle wedge, implying regional-scale surface uplift (or reduced subsidence) and magmatic quiescence, respectively. We identify two episodes of Mesozoic flat slabs below East Asia, one during the Jurassic-Early Cretaceous and the other during the Late Cretaceous. The former affected the eastern half of North China and Northeast China, and the latter affected the entire region east of the NSGL from Northeast China to South China. These two flat-slab cycles largely determined the evolution of the lithosphere and topography within East Asia since the Mesozoic.
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Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit ...phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.
Arc volcanism, crustal deformation, and their interplay are poorly understood in northwestern Sumatra. Traditional receiver function H‐κ stacking studies constrain the variations in crustal thickness ...and Vp/Vs ratio in volcanic zones but rarely estimate the melt fractions. Here, we propose a H‐Φ stacking method, a variant of the H‐κ stacking method, and apply it to the dense nodal array data from Aceh, northern Sumatra, to estimate crustal thickness, Vp/Vs ratio, and melt fraction. Most results show considerably high Vp/Vs ratios (∼1.98) and melt fractions (up to 19%), indicating pervasive crustal magmatic mush. The northwestern edge of the Aceh crust is much thinner (∼22 km) than extended crust globally, reflecting a highly stretched crust due to tectonic processes governing the opening of the Andaman Sea. This thin crust and high melt fractions explain the Bouguer gravity anomaly, and partly explain the northward migration of Quaternary volcanics.
Plain Language Summary
Crustal thickness and melt fraction are important indicators of crustal magmatism and deformation. Situated between the Sumatran and Andaman subduction zones, Aceh, in northwestern Sumatra, is distinguished by strong crustal deformation, resulting in active crustal seismicity, and Quaternary volcanics that have migrated northward over time. However, the abnormal arc volcanism, crustal deformation, and their interplay, remain unclear because of poor understanding of the crustal structure. To fill this knowledge gap, we deployed 155 nodal seismic stations in Aceh for 18 months. In this work, we develop a new receiver function method that takes advantage of converted seismic energy from the base of the crust to constrain the crustal thickness and melt fraction beneath the stations in Aceh. We find that: (a) the average crustal melt fraction is as high as 19%, indicating a considerable volume of partially molten rock in the crust and (b) the crust in northern Aceh is as thin as ∼22 km, suggesting high stretching of the crust associated with the opening of the Andaman Sea. The stretched crust with a high melt fraction partly explains the northward migration of Quaternary volcanics and active seismicity/crustal deformation, but the migration mechanism of other volcanics requires further investigation.
Key Points
A new receiver function method is developed to constrain crustal thickness and melt fraction
Applications to dense nodal array data in northwestern Sumatra show a thin (∼22 km) crust and high crustal melt fraction (up to 19%)
The new constraints partly explain abnormal volcanic migration and crustal stretching
Cancer immunotherapy has revolutionized the paradigm for the clinical management of cancer. While FDA-approved cancer immunotherapies thus far mainly exploit the adaptive immunity for therapeutic ...efficacy, there is a growing appreciation for the importance of innate immunity in tumor cell surveillance and eradication. The past decade has witnessed macrophages being thrust into the spotlight as critical effectors of an innate anti-tumor response. Promising evidence from preclinical and clinical studies have established targeting macrophage phagocytosis as an effective therapeutic strategy, either alone or in combination with other therapeutic moieties. Here, we review the recent translational advances in harnessing macrophage phagocytosis as a pivotal therapeutic effort in cancer treatment. In addition, this review emphasizes phagocytosis checkpoint blockade and the use of nanoparticles as effective strategies to potentiate macrophages for phagocytosis. We also highlight chimeric antigen receptor macrophages as a next-generation therapeutic modality linking the closely intertwined innate and adaptive immunity to induce efficacious anti-tumor immune responses.
Significance Macrophage-mediated programmed cell removal (PrCR) plays an essential role in tumor surveillance and elimination. Blockade of the don't-eat-me signal CD47 on tumor cells allows already ...expressed eat-me signals to induce PrCR to eliminate tumor cells. To date the molecular mechanism by which macrophages recognize and phagocytose tumor cells remains unclear. This paper demonstrates that the activation of Toll-like receptor (TLR) pathways in macrophages induces the phosphorylation of Bruton's tyrosine kinase (Btk), which catalyzes cell-surface exposure of calreticulin. Calreticulin on or secreted by macrophages plays a critical role in mediating adjacent tumor cell recognition and phagocytosis. These findings reveal a strategy to enhance the efficacy of PrCR through a combination of TLR/Btk activation and CD47 blockade, and advance our understanding of the underlying mechanism of macrophage-mediated PrCR of tumor cells.
Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don’t-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages. Here we demonstrate that the activation of Toll-like receptor (TLR) signaling pathways in macrophages synergizes with blocking CD47 on tumor cells to enhance PrCR. Bruton’s tyrosine kinase (Btk) mediates TLR signaling in macrophages. Calreticulin, previously shown to be an eat-me signal on cancer cells, is activated in macrophages for secretion and cell-surface exposure by TLR and Btk to target cancer cells for phagocytosis, even if the cancer cells themselves do not express calreticulin.
Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate ...target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR. Importantly, we identified asialoglycans on the target cells to which CRT binds to regulate PrCR, and the availability of such CRT-binding sites on cancer cells correlated with the prognosis of patients in various malignancies. Our study reveals a general mechanism of target cell recognition by macrophages, which is the key for the removal of unwanted cells by PrCR in physiological and pathophysiological processes.
GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment ...inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-G
signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual G
-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
GABRR1 is a rho subunit receptor of GABA, the major inhibitory neurotransmitter in the mammalian brain. While most investigations of its function focused on the nervous system, its regulatory role in ...hematopoiesis has not been reported. In this study, we found GABRR1 is mainly expressed on subsets of human and mouse hematopoietic stem cells (HSCs) and megakaryocyte progenitors (MkPs). GABRR1-negative (GR−) HSCs led to higher donor-derived hematopoietic chimerism than GABRR1-positive (GR+) HSCs. GR+ but not GR− HSCs and MkPs respond to GABA in patch clamp studies. Inhibition of GABRR1 via genetic knockout or antagonists inhibited MkP differentiation and reduced platelet numbers in blood. Overexpression of GABRR1 or treatment with agonists significantly promoted MkP generation and megakaryocyte colonies. Thus, this study identifies a link between the neural and hematopoietic systems and opens up the possibility of manipulating GABA signaling for platelet-required clinical applications.
Staphylococcus aureus is a major pathogen of varieties of oral mucous infection. Prostaglandin E2 (PGE2) is a pro-inflammatory factor and Cyclooxygenase 2 (COX-2) is a critical enzyme of PGE2 ...biosynthesis. The purpose of this study is to investigate whether Staphylococcus aureus can increase PGE2 production of oral epithelial cells and how PGE2 functions in the growth and adherence of Staphylococcus aureus. mRNA levels of COX-2, fnbpA and fnbpB were estimated by quantitative PCR. PGE2 production was measured by Enzyme Linked Immunosorbent Assay (ELISA). The binding biomass of Staphylococcus aureus to human fibronectin was investigated by crystal violet staining and confocal laser scanning microscopy and the adherent force was measured by atomic force microscope (AFM). The COX-2 mRNA level and PGE2 production were increased by Staphylococcus aureus. PGE2 promoted the growth and biofilm formation of Staphylococcus aureus, enhanced the attachment of Staphylococcus aureus to the human fibronectin as well as to the HOK cells. The transcription of fnbpB was up-regulated by PGE2 in both early and middle exponential phase but not fnbpA. These results suggest that the activation of COX-2/PGE2 pathway in oral epithelial cell by Staphylococcus aureus can in turn facilitate the growth and the ability to adhere of the pathogen. These findings uncover a new function of PGE2 and may lead to the potential of COX-2/PGE2 targeting in the therapy of inflammation and cancer in both which the COX-2/PGE2 pathway were observed activated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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