Marc C.PulancoAnne T.MadsenAnkit TanwarDevin T.Corrigan...
694-713页
查看更多>>摘要：The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various diseases.Recent basic and clinical studies have revealed novel biology of the B7/CD28 families and new therapeutics for cancer therapy.In this review,we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways,PD-1/PD-L1 and B7-H3 as metabolic regulators,the glycobiology of PD-1/PD-L1,B7x(B7-H4)and B7-H3,and the recently characterized PD-L1/B7-1 cis-interaction.We also cover the tumor-intrinsic and-extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical settings.Finally,we review new immunotherapies targeting B7-H3,B7x,PD-1/PD-L1,and CTLA-4 in current clinical trials.
查看更多>>摘要：Breast cancer is the most prevalent cancer worldwide,and metastasis is the leading cause of death in cancer patients.Human monocyte chemoattractant protein-1(MCP-1/CCL2)was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes.MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages(TAMs),and it became a candidate target of clinical intervention;however,the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1.The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues,including breast cancers.Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established.The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung,bone,and brain was examined in mouse breast cancer models.The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone.Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported.In the present manuscript,we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis.
查看更多>>摘要：Over the past thirty years,the importance of chemokines and their seven-transmembrane G protein-coupled receptors(GPCRs)has been increasingly recognized.Chemokine interactions with receptors trigger signaling pathway activity to form a network fundamental to diverse immune processes,including host homeostasis and responses to disease.Genetic and nongenetic regulation of both the expression and structure of chemokines and receptors conveys chemokine functional heterogeneity.Imbalances and defects in the system contribute to the pathogenesis of a variety of diseases,including cancer,immune and inflammatory diseases,and metabolic and neurological disorders,which render the system a focus of studies aiming to discover therapies and important biomarkers.The integrated view of chemokine biology underpinning divergence and plasticity has provided insights into immune dysfunction in disease states,including,among others,coronavirus disease 2019(COVID-19).In this review,by reporting the latest advances in chemokine biology and results from analyses of a plethora of sequencing-based datasets,we outline recent advances in the understanding of the genetic variations and nongenetic heterogeneity of chemokines and receptors and provide an updated view of their contribution to the pathophysiological network,focusing on chemokine-mediated inflammation and cancer.Clarification of the molecular basis of dynamic chemokine-receptor interactions will help advance the understanding of chemokine biology to achieve precision medicine application in the clinic.
查看更多>>摘要：As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57+CD4+T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples.Circulating CD57+ CD4+ T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a pre-exhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57+ CD4+ T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4+ T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.
查看更多>>摘要：Interleukin-33(IL-33)is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis.The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation,but the mechanism is still unclear.Here,we found that healthy individuals had higher phosphate-pyridoxal(PLP,an active form of vitamin B6)concentrations in the serum than asthma patients.Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation.In a mouse model of lung inflammation,we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33.A mechanistic study showed that in vivo,pyridoxal(PL)needed to be converted into PLP,which inhibited the type 2 response by regulating IL-33 stability.In mice heterozygous for pyridoxal kinase(PDXK),the conversion of PL to PLP was limited,and IL-33 levels were increased in the lungs,aggravating type 2 inflammation.Furthermore,we found that the mouse double minute 2 homolog(MDM2)protein,an E3 ubiquitin-protein ligase,could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells.PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway.In addition,inhalation of PLP alleviated asthma-related effects in mouse models.In summary,our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response,which might help develop a potential preventive and therapeutic agent for allergy-related diseases.
查看更多>>摘要：Innate lymphoid cells(ILCs)are the counterpart of T helper cells in the innate immune system and share multiple phenotypes with T helper cells.Inducible T-cell costimulator(ICOS)is recognized on T cells and participates in T-cell activation and T and B-cell engagement in lymphoid tissues.However,the role of ICOS in ILC3s and ILC3-involved interactions with the immune microenvironment remains unclear.Here,we found that ICOS expression on human ILC3s was correlated with the activated state of ILC3s.ICOS costimulation enhanced the survival,proliferation,and capacity of ILC3s to produce cytokines(IL-22,IL-17A,IFN-γ,TNF,and GM-CSF).Via synergistic effects of ICOS and CD40 signaling,B cells promoted ILC3 functions,and ILC3-induced T-cell-independent B-cell IgA and IgM secretion primarily required CD40 signaling.Hence,ICOS is essential for the nonredundant role of ILC3s and their interaction with adjacent B cells.
查看更多>>摘要：Recombinant interleukin-33(IL-33)inhibits tumor growth,but the detailed immunological mechanism is still unknown.IL-33-mediated tumor suppression did not occur in Batf3-/-mice,indicating that conventional type 1 dendritic cells(cDC1s)play a key role in IL-33-mediated antitumor immunity.A population of CD103+ cDC1s,which were barely detectable in the spleens of normal mice,increased significantly in the spleens of IL-33-treated mice.The newly emerged splenic CD103+ cDC1s were distinct from conventional splenic cDC1s based on their spleen residency,robust effector T-cell priming ability,and surface expression of FCGR3.DCs and DC precursors did not express Suppressor of Tumorigenicity 2(ST2).However,recombinant IL-33 induced spleen-resident FCGR3+CD103+ cDC1s,which were found to be differentiated from DC precursors by bystander ST2+ immune cells.Through immune cell fractionation and depletion assays,we found that IL-33-primed ST2+ basophils play a crucial role in the development of FCGR3+CD103+ cDC1s by secreting IL-33-driven extrinsic factors.Recombinant GM-CSF also induced the population of CD103+ cDC1s,but the population neither expressed FCGR3 nor induced any discernable antitumor immunity.The population of FCGR3+CD103+ cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs(FL-BMDCs)when IL-33 was added in a pre-DC stage of culture.FL-BMDCs generated in the presence of IL-33(FL-33-DCs)offered more potent tumor immunotherapy than control Flt3L-BMDCs(FL-DCs).Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors.Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.
查看更多>>摘要：Early and strong interferon type I(IFN-I)responses are usually associated with mild COVID-19 disease,whereas persistent or unregulated proinflammatory cytokine responses are associated with severe disease outcomes.Previous work suggested that monocyte-derived macrophages(MDMs)are resistant and unresponsive to SARS-CoV-2 infection.Here,we demonstrate that upon phagocytosis of SARS-CoV-2-infected cells,MDMs are activated and secrete IL-6 and TNF.Importantly,activated MDMs in turn mediate strong activation of plasmacytoid dendritic cells(pDCs),leading to the secretion of high levels of IFN-α and TNF.Furthermore,pDC activation promoted IL-6 production by MDMs.This kind of pDC activation was dependent on direct integrin-mediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways.Overall,the present study describes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells.These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses,which may contribute to tissue damage and severe disease.
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