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International Immunopharmacology Jun 2024Immune checkpoint therapy (ICT) has been shown to produce durable responses in various cancer patients. However, its efficacy is notably limited in hepatocellular...
Immune checkpoint therapy (ICT) has been shown to produce durable responses in various cancer patients. However, its efficacy is notably limited in hepatocellular carcinoma (HCC), with only a small percentage of patients responding positively to treatment. The mechanism underlying resistance to ICT in HCC remains poorly understood. Here, we showed that combination treatment of ICG-001, an inhibitor of the Wnt/β-catenin signaling pathway, with anti-PD-1 antibody effectively suppresses tumor growth and promotes the infiltration of immune cells such as DCs and CD8 T cells in the tumor microenvironment (TME). By inhibiting the activity of β-catenin and blocking its binding to the transcription factor IKAROS family zinc finger 1 (IKZF1), ICG-001 upregulated the expression of CCL5. Moreover, IKZF1 regulated the activity of the CCL5 promoter and its endogenous expression. Through inhibition of the WNT/β-catenin signaling pathway, upregulation of the expression of CCL5 was achieved, which subsequently recruited more DCs into the TME via C-C motif chemokine receptor 5 (CCR5). This, in turn, resulted in an increase in the infiltration of CD8 T cells in the TME, thereby enhancing the antitumor immune response. Analysis of a tissue microarray derived from HCC patient samples revealed a positive correlation between survival rate and prognosis and the expression levels of CCL5/CD8. In conclusion, our findings suggest that combined application of ICG-001 and anti-PD-1 antibody exhibits significantly enhanced antitumor efficacy. Hence, combining a WNT/β-catenin signaling pathway inhibitor with anti-PD-1 therapy may be a promising treatment strategy for patients with HCC.
PubMed: 38941667
DOI: 10.1016/j.intimp.2024.112534 -
Annual Review of Immunology Jun 2024The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities... (Review)
Review
The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Topics: Humans; Immunity, Innate; COVID-19; SARS-CoV-2; Cytokine Release Syndrome; Cytokines; Animals; Coronavirus Infections; Immune Evasion
PubMed: 38941608
DOI: 10.1146/annurev-immunol-083122-043545 -
Annual Review of Immunology Jun 2024Poxviruses have evolved a wide array of mechanisms to evade the immune response, and we provide an overview of the different immunomodulatory strategies. Poxviruses... (Review)
Review
Poxviruses have evolved a wide array of mechanisms to evade the immune response, and we provide an overview of the different immunomodulatory strategies. Poxviruses prevent the recognition of viral DNA that triggers the immune responses and inhibit signaling pathways within the infected cell. A unique feature of poxviruses is the production of secreted proteins that mimic cytokines and cytokine receptors, acting as decoy receptors to neutralize the activity of cytokines and chemokines. The capacity of these proteins to evade cellular immune responses by inhibiting cytokine activation is complemented by poxviruses' strategies to block natural killer cells and cytotoxic T cells, often through interfering with antigen presentation pathways. Mechanisms that target complement activation are also encoded by poxviruses. Virus-encoded proteins that target immune molecules and pathways play a major role in immune modulation, and their contribution to viral pathogenesis, facilitating virus replication or preventing immunopathology, is discussed.
Topics: Humans; Poxviridae; Immune Evasion; Animals; Poxviridae Infections; Cytokines; Signal Transduction; Viral Proteins; Antigen Presentation; Host-Pathogen Interactions
PubMed: 38941604
DOI: 10.1146/annurev-immunol-090222-110227 -
Annual Review of Immunology Jun 2024Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic... (Review)
Review
Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic acids through endosomal Toll-like receptors and the ensuing production of type I interferon and other soluble mediators, which orchestrate innate and adaptive responses. We review several aspects of pDC biology that have recently come to the fore. We discuss emerging questions regarding the lineage affiliation and origin of pDCs and argue that these cells constitute an integral part of the dendritic cell lineage. We emphasize the specific function of pDCs as innate sentinels of virus infection, particularly their recognition of and distinct response to virus-infected cells. This essential evolutionary role of pDCs has been particularly important for the control of coronaviruses, as demonstrated by the recent COVID-19 pandemic. Finally, we highlight the key contribution of pDCs to systemic lupus erythematosus, in which therapeutic targeting of pDCs is currently underway.
Topics: Dendritic Cells; Humans; COVID-19; Animals; Immunity, Innate; SARS-CoV-2; Lupus Erythematosus, Systemic; Toll-Like Receptors; Cell Differentiation; Cell Lineage
PubMed: 38941603
DOI: 10.1146/annurev-immunol-090122-041105 -
International Journal of Circumpolar... Dec 2024serotype a (Hia) has recently emerged as an important cause of invasive disease in the North American Arctic and Sub-Arctic regions, mainly affecting young Indigenous...
serotype a (Hia) has recently emerged as an important cause of invasive disease in the North American Arctic and Sub-Arctic regions, mainly affecting young Indigenous children. In this study, we addressed the question of whether the prevalence of Hia and all in the nasopharynx differed between paediatric populations from regions with high low incidence of invasive Hia disease. Nasopharyngeal specimens from children with acute respiratory tract infections (ARTI) collected for routine diagnostic detection of respiratory viruses were analysed with molecular-genetic methods to identify and serotype . In Nunavut, a region with a high incidence of invasive Hia disease, all and particularly Hia were found in the nasopharynx of 60.6% and 3.0% children. In Southern Ontario (Hamilton region), where Hia invasive disease is rare, the frequencies of all and Hia detection were 38.5% and 0.6%, respectively. In both cohorts, non-typeable was prevalent (57.0% and 37.9%, respectively). Considering that Hia is an important cause of severe invasive disease in Nunavut children, 3% prevalence of Hia among children with ARTI can reflect continuing circulation of the pathogen in the Northern communities that may result in invasive disease outbreaks.
Topics: Humans; Haemophilus influenzae; Haemophilus Infections; Child, Preschool; Nasopharynx; Prevalence; Infant; Male; Female; Incidence; Ontario; Child; Arctic Regions; Nunavut; Respiratory Tract Infections; Canada; Serogroup
PubMed: 38941555
DOI: 10.1080/22423982.2024.2371111 -
Blood Advances Jun 2024In utero hematopoietic cell transplantation (IUHCT) is an experimental non-myeloablative therapy with potential application to hematologic disorders including Sickle...
In utero hematopoietic cell transplantation (IUHCT) is an experimental non-myeloablative therapy with potential application to hematologic disorders including Sickle cell disease. Its clinical utility has been limited due to the early acquisition of T cell immunity beginning at approximately 14 weeks gestation, posing significant technical challenges and excluding from treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days post-coitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable to the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T cell depletion followed by central tolerance induction confirmed by donor-specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrate successful application of this approach to the Townes mouse model of Sickle cell disease. These findings confirm the developing fetal T cell response as a barrier to LGT and support transient T cell depletion as a safe and effective immunomodulatory strategy by which to overcome it.
PubMed: 38941538
DOI: 10.1182/bloodadvances.2023012247 -
Integrative Zoology Jun 2024Overview of Hemocytin-Mediated Cellular Encapsulation and Melanization Responses in Insects Against Fungal Pathogens.
Overview of Hemocytin-Mediated Cellular Encapsulation and Melanization Responses in Insects Against Fungal Pathogens.
PubMed: 38941499
DOI: 10.1111/1749-4877.12867 -
Science Immunology Jun 2024KLRG1 CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against...
KLRG1 CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1 memory subsets such as central and effector memory T cells. Thus, KLRG1 memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1 or KLRG1 memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.
Topics: Animals; Receptors, Immunologic; Mice; Lectins, C-Type; Mice, Inbred C57BL; Memory T Cells; Immunologic Memory; CD8-Positive T-Lymphocytes; Female; Mice, Knockout
PubMed: 38941479
DOI: 10.1126/sciimmunol.adj8356 -
The Plant Cell Jun 2024Plants possess a robust and sophisticated innate immune system against pathogens and must balance growth with rapid pathogen detection and defense. The intracellular...
Plants possess a robust and sophisticated innate immune system against pathogens and must balance growth with rapid pathogen detection and defense. The intracellular receptors with nucleotide-binding leucine-rich repeat (NLR) motifs recognize pathogen-derived effector proteins and thereby trigger the immune response. The expression of genes encoding NLR receptors is precisely controlled in multifaceted ways. The alternative splicing (AS) of introns in response to infection is recurrently observed but poorly understood. Here we report that the potato (Solanum tuberosum) NLR gene RB undergoes AS of its intron, resulting in two transcriptional isoforms, which coordinately regulate plant immunity and growth homeostasis. During normal growth, RB predominantly exists as intron-retained isoform RB_IR, encoding a truncated protein containing only the N-terminus of the NLR. Upon late blight infection, the pathogen induces intron splicing of RB, increasing the abundance of RB_CDS, which encodes a full-length and active R protein. By deploying the RB splicing isoforms fused with a luciferase reporter system, we identified IPI-O1 (also known as Avrblb1), the RB cognate effector, as a facilitator of RB AS. IPI-O1 directly interacts with potato splicing factor StCWC15, resulting in altered localization of StCWC15 from the nucleoplasm to the nucleolus and nuclear speckles. Mutations in IPI-O1 that eliminate StCWC15 binding also disrupt StCWC15 re-localization and RB intron splicing. Thus, our study reveals that StCWC15 serves as a surveillance facilitator that senses the pathogen-secreted effector and regulates the trade-off between RB-mediated plant immunity and growth, expanding our understanding of molecular plant-microbe interactions.
PubMed: 38941447
DOI: 10.1093/plcell/koae189 -
Medicine Jun 2024Surgical site infection (SSI) after posterior open lumbar fusion (POLF) is a major concern for both surgeons and patients. We sought to explore whether local application... (Observational Study)
Observational Study
Surgical site infection (SSI) after posterior open lumbar fusion (POLF) is a major concern for both surgeons and patients. We sought to explore whether local application of vancomycin could decrease the rate of SSI. We reviewed the clinical data of patients who underwent POLF between June 2015 and June 2022 at 3 spinal centers. Patients were divided into those who received local vancomycin (vancomycin group) and those who did not (non-vancomycin group). The SSI rates at 12 months postoperatively were compared between the 2 groups. Although a trend toward a lower infection rate was observed in the vancomycin group than in the non-vancomycin group; the difference was not statistically significant (3.6% vs 5.5%, P = .121). However, we found that the postoperative SSI rate was significantly lower in the vancomycin group than in the non-vancomycin group (4.9% vs 11.4%, P = .041) in patients ≥ 2 fused segments, while there was no significant difference in postoperative SSI rate in patients with single fusion segment (3.1% vs 3.6%, P = .706). The logistic regression analysis indicated that the SSI rate in the non-vancomycin group was approximately 2.498 times higher than that in the vancomycin group (P = .048, odds ratio: 2.498, 95% confidence interval: 1.011-6.617) in patients with ≥2 fused segments. In SSI patients with confirmed pathogens, the SSI rate of Gram-negative bacteria in the vancomycin group was significantly higher than that in the non-vancomycin group (10/14 [71.4%] vs 5/22 [31.8%]), whereas the SSI rate of Gram-positive bacteria in the vancomycin group was significantly lower than that in the non-vancomycin group (4/14 [28.6%] vs 15/22 [68.2%]). Local administration of vancomycin is recommended in patients with ≥2 fused segments as it may facilitate to reduce the postoperative rate of SSI after POLF. Additionally, the local use of vancomycin can decrease the Gram-positive bacterial infections but is not effective against Gram-negative infections, which indirectly leads to an increase in the proportion of Gram-negative infections in SSI patients with confirmed pathogens.
Topics: Humans; Vancomycin; Surgical Wound Infection; Spinal Fusion; Retrospective Studies; Male; Female; Middle Aged; Anti-Bacterial Agents; Aged; Lumbar Vertebrae; Adult
PubMed: 38941406
DOI: 10.1097/MD.0000000000038664