Cell Surface Immune Receptors Research Articles

Engineering a conserved immune coreceptor into a primed state enhances fungal resistance in crops without growth penalty.

Plants must tactically balance immunity and growth when combating lethal pathogens like fungi. CHITIN ELICITOR RECEPTOR KINASE 1 (CERK1), a conserved cell-surface co-receptor for the fungal elicitor chitin, enables plants to induce chitin-triggered immunity to counteract fungal invasion. Previously, we reported that bacterial infection can prime CERK1 through juxtamembrane (JM) phosphorylation to enhance fungal resistance, which only occurs in Arabidopsis (Arabidopsis thaliana) and its close relatives in Brassicaceae. Here, we aim to transfer the priming mechanism of Arabidopsis CERK1 (AtCERK1) to crop CERK1 via JM substitution. We revealed in protoplasts that the entire AtCERK1 JM variable region (AtJM) is essential for imparting the bacterial elicitor flg22-induced primed state to the Nicotiana benthamiana CERK1 (NbCERK1). The NbCERK1 chimera containing AtJM (NbCERK1AtJM) and similarly constructed rice (Oryza sativa) OsCERK1AtJM could undergo flg22-induced JM phosphorylation and confer enhanced antifungal immunity upon bacterial co-infection. Moreover, the NbCERK1AtJM+3D derivative with AtJM phosphomimetic mutations to mimic a constant primed state and similarly constructed OsCERK1AtJM+3D were sufficient to mediate strengthened chitin responses and fungal resistance in transgenic plants independent of bacterial infection. Importantly, no growth and reproduction defects were observed in these plants. Taken together, this study demonstrates that manipulating the primed state of a cell-surface immune receptor offers an effective approach to improve disease resistance in crops without compromising growth and yield and showcases how fundamental insights in plant biology can be translated into crop breeding applications.

Single-cell profiling of response to neoadjuvant chemo-immunotherapy in surgically resectable esophageal squamous cell carcinoma

BackgroundThe efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients.MethodsWe analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR).ResultsSingle-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell–cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC.ConclusionsThis pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.

Abstract 5560: Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach

Abstract Secreted protein acidic and rich in cysteine (SPARC), is a multifunction protein that interacts with extracellular matrix (ECM), cell surface receptors, and signaling molecules. These interactions in cancer cells result in less susceptible of cells to the immune system, leading to poor prognosis. SPARC plays a crucial role in transporting collagen, a significant component of the ECM, from the site of synthesis to the basement membrane of the cells. Collagen mediated rigidity enhancement of cell microenvironment promotes cancer cell growth, proliferation, and angiogenesis. Collagen remodeling plays a complex and multifaceted role in cancer immunomodulation. Our current research focuses on exploring the cancer treatment mechanism by immunomodulation based on SPARC and collagen through theoretical and computational approaches. Our previous investigations identified SPARC and collagen as potential biomarkers for targeting cancer cells. Our current theoretical research identifies the role of SPARC and collagen in tuning the tumor microenvironment and altering the immune system cell surface receptors. This theoretical investigation is followed by computational study to formulate the pathway from secretions of both SPARC and collagen to reprogramming of tumor microenvironment. SPARC and collagen’s effects on the cell immune system are analyzed by performing molecular interaction and molecular dynamics studies for SPARC and collagen with the cell surface receptors. From our study, we identify the cellular mechanisms involved either actively or passively in the progression and prognosis of the cancer. Our study will provide insight into a novel pathway for targeting the cancer microenvironment, which will be helpful in the formation of low-dosage cancer drugs, resulting in the decreased adverse effects of drugs and increased patient quality of life. Citation Format: Ramakrishna Prasad Are, Anju R Babu. Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5560.

Extracellular perception of multiple novel core effectors from the broad host-range pear anthracnose pathogen Colletotrichum fructicola in the nonhost Nicotiana benthamiana.

Colletotrichum fructicola is emerging as a devastating pathogenic fungus causing anthracnose in a wide range of horticultural crops, particularly fruits. Exploitation of nonhost resistance (NHR) represents a robust strategy for plant disease management. Perception of core effectors from phytopathogens frequently leads to hypersensitive cell death and resistance in nonhost plants; however, such core effectors in C. fructicola and their signaling components in non-hosts remain elusive. Here, we found a virulent C. fructicola strain isolated from pear exhibits non-adaptation in the model plant Nicotiana benthamiana. Perception of secreted molecules from C. fructicola appears to be a dominant factor in NHR, and four novel core effectors-CfCE4, CfCE25, CfCE61, and CfCE66-detected by N. benthamiana were, accordingly, identified. These core effectors exhibit cell death-inducing activity in N. benthamiana and accumulate in the apoplast. With a series of CRISPR/Cas9-edited mutants or gene-silenced plants, we found the coreceptor BAK1 and helper NLRs including ADR1, NRG1, and NRCs mediate perceptions of these core effectors in N. benthamiana. Concurrently, multiple N. benthamiana genes encoding cell surface immune receptors and intracellular immune receptors were greatly induced by C. fructicola. This work represents the first characterization of the repertoire of C. fructicola core effectors responsible for NHR. Significantly, the novel core effectors and their signaling components unveiled in this study offered insights into a continuum of layered immunity during NHR and will be helpful for anthracnose disease management in diverse horticultural crops.

The Identification Distinct Antiviral Factors Regulated Influenza Pandemic H1N1 Infection.

Influenza pandemic with H1N1 (H1N1pdms) causes severe lung damage and "cytokine storm," leading to higher mortality and global health emergencies in humans and animals. Explaining host antiviral molecular mechanisms in response to H1N1pdms is important for the development of novel therapies. In this study, we organised and analysed multimicroarray data for mouse lungs infected with different H1N1pdm and nonpandemic H1N1 strains. We found that H1N1pdms infection resulted in a large proportion of differentially expressed genes (DEGs) in the infected lungs compared with normal lungs, and the number of DEGs increased markedly with the time of infection. In addition, we found that different H1N1pdm strains induced similarly innate immune responses and the identified DEGs during H1N1pdms infection were functionally concentrated in defence response to virus, cytokine-mediated signalling pathway, regulation of innate immune response, and response to interferon. Moreover, comparing with nonpandemic H1N1, we identified ten distinct DEGs (AREG, CXCL13, GATM, GPR171, IFI35, IFI47, IFIT3, ORM1, RETNLA, and UBD), which were enriched in immune response and cell surface receptor signalling pathway as well as interacted with immune response-related dysregulated genes during H1N1pdms. Our discoveries will provide comprehensive insights into host responding to pandemic with influenza H1N1 and find broad-spectrum effective treatment.

INPP5D is associated with tau seeding and tau pathogenesis

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia characterized by extracellular amyloid deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau aggregates. GWAS studies have identified variants in several inflammatory genes as significant risk factors for AD, highlighting that neuroinflammation is a critical, underlying pathological component in AD. INPP5D, a family member of Src homology 2 domain containing inositol 5' polyphosphatases (SHIPs), is an AD risk gene related to innate immunity in late‐onset AD (LOAD). Inpp5d plays a role in regulating signal transduction initiated by immune cell surface receptors. INPP5D binds receptor ITIMs, competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P¬2, thereby limiting downstream signaling. We previously reported that Inpp5d expression is increased in LOAD and is positively correlated with amyloid burden. However, the relationship of Inpp5d in tau pathology remains unclear. We hypothesize that inhibiting INPP5D will release the break and increase microglial function.MethodsTo assess the role of Inpp5d in tau pathology, we performed a fluorescence resonance energy transfer (FRET) assay on human‐AD brains obtained from NCRAD. We also crossed a mouse model deficient in Inpp5d (Inpp5d+/−) with a PS19 model of tau pathology and measured tau phosphorylation and transcriptomics. Primary microglia were utilized to measure microglial internalization of Tau.ResultsIn human AD‐ brains, increased tau seeding was positively correlated with Inpp5d expression. Furthermore, in PS19 mice, Inpp5d protein expression was upregulated and positively correlated with phosphorylated tau (S202, Thr205). Utilizing the NanoString nCounter assay, we found an upregulation of the immune‐related and cell migration related genes in PS19.Inpp5d+/‐ mice compared to PS19 mice. Primary microglia from Inpp5d+/− mice released increased tau internalization compared to WT microglia.ConclusionOur findings confirmed that elevated Inpp5d expression in human‐AD subjects is recapitulated in PS19 mice and correlated with increased tau pathology. In PS19.Inpp5d+/‐ mice we found alterations in immune related and cell migration related pathways suggesting that Inpp5d modulates the disease progression through these pathways. Furthermore, pathogenesis may be modulated through increased internalization of tau. Together these results suggest that therapeutic interventions aimed at reducing Inpp5d may be beneficial in tauopathies.

ROS and RNS production, subcellular localization, and signaling triggered by immunogenic danger signals.

Plants continuously monitor the environment to detect changing conditions and to properly respond, avoiding deleterious effects on their fitness and survival. An enormous number of cell surface and intracellular immune receptors are deployed to perceive danger signals associated with microbial infections. Ligand binding by cognate receptors represents the first essential event in triggering plant immunity and determining the outcome of the tissue invasion attempt. Reactive oxygen and nitrogen species (ROS/RNS) are secondary messengers rapidly produced in different subcellular localizations upon the perception of immunogenic signals. Danger signal transduction inside the plant cells involves cytoskeletal rearrangements as well as several organelles and interactions between them to activate key immune signaling modules. Such immune processes depend on ROS and RNS accumulation, highlighting their role as key regulators in the execution of the immune cellular program. In fact, ROS and RNS are synergic and interdependent intracellular signals required for decoding danger signals and for the modulation of defense-related responses. Here we summarize current knowledge on ROS/RNS production, compartmentalization, and signaling in plant cells that have perceived immunogenic danger signals.

Repurposing Fc gamma receptor I (FcγRI, CD64) for site-oriented monoclonal antibody capture: A proof-of-concept study for real-time detection of tumor necrosis factor-alpha (TNF -α)

The controlled orientation of biomolecules on the sensor surface is crucial for achieving high sensitivity and accurate detection of target molecules in biosensing. FcγRI is an immune cell surface receptor for recognizing IgG-coated targets, such as opsonized pathogens or immune complexes. It plays a crucial role in T cell activation and internalization of the cargos, leading downstream signaling cascades. In this study, we repurposed the FcγRI as an analytical ligand molecule for site-oriented ADA capture, a monoclonal antibody-based biosimilar drug, on a plasmonic sensor surface and demonstrated the real-time detection of the corresponding analyte molecule, TNF-α. The study encompasses the analysis of comparative ligand behaviors on the surface, biosensor kinetics, concentration-dependent studies, and sensor specificity assays. The findings of this study suggest that FcγRI has a significant potential to serve as a universal ligand molecule for site-specific monoclonal antibody capture, and it can be used for biosensing studies, as it represents low nanomolar range affinity and excellent selectivity towards the target. However, there is still room for improvement in the surface stability and sensing response, and further studies are needed to reveal its performance on the monoclonal antibodies with various antigen binding sites and glycoforms.

Role of the membrane-spanning 4A gene family in lung adenocarcinoma.

Lung adenocarcinoma, which is the second most prevalent cancer in the world, has a poor prognosis and a low 5-year survival rate. The MS4A protein family is crucial to disease development and progression, particularly for cancers, allergies, metabolic disorders, autoimmune diseases, infections, and neurodegenerative disorders. However, its involvement in lung adenocarcinoma remains unclear. In this study, we found that 11 MS4A family genes were upregulated or downregulated in lung adenocarcinoma. Furthermore, we described the genetic variation landscape of the MS4A family in lung adenocarcinoma. Notably, through functional enrichment analysis, we discovered that the MS4A family is involved in the immune response regulatory signaling pathway and the immune response regulatory cell surface receptor signaling pathway. According to the Kaplan-Meier curve, patients with lung adenocarcinoma having poor expression of MS4A2, MS4A7, MS4A14, and MS4A15 had a low overall survival rate. These four prognostic genes are substantially associated with immune-infiltrating cells, and a prognosis model incorporating them may more accurately predict the overall survival rate of patients with lung adenocarcinoma than current models. The findings of this study may offer creative suggestions and recommendations for the identification and management of lung adenocarcinoma.

Overexpression of POLA2 in hepatocellular carcinoma is involved in immune infiltration and predicts a poor prognosis

BackgroundHepatocellular carcinoma (HCC) is the second malignancy worldwide. POLA2 initiates DNA replication, regulates cell cycle and gene repair that promote tumorigenesis and disease progression. However, the prognostic and biological function roles of POLA2 in HCC had not been conclusively determined.MethodsThe expression levels and prognosis role of POLA1 and POLA2 in HCC were analyzed based on TCGA-LIHC database and recruited 24 HCC patients. Gene mutations were analyzed using “maftools” package. POLA2 and immune cells correlations were analyzed by TIMER. POLA2 co-expressed genes functional enrichment were evaluated using Metascape. The mRNA and protein level of POLA2 was detected in HCC cells and tissues. Cell migration, invasion, proliferation, cell cycle and HCC cell lines derived xenograft model were performed to investigate POLA2 biological function.ResultsPOLA2 was significantly high expressed in HCC than in normal liver tissue in both TCGA-LIHC and our collected HCC samples. In validation cohort, POLA2 significantly related to tumor differentiation, tumor size and Ki-67 (p < 0.05). In TCGA-LIHC cohort, overexpression of POLA2 predicted a low OS and associated with different clinical stages. Multivariate Cox regression showed overexpression of POLA2 effectively distinguished the prognosis at different T, N, M, stages and grades of HCC. POLA2 expression correlated with mutation burden, immune cells infiltration and immune-associated genes expression of HCC. Functional enrichment revealed that POLA2 co-expressed genes were linked to cellular activity, plasma membrane protein complex and leukocyte activity, immune response-regulated cell surface receptor signaling pathway, and immune response-regulated signaling pathway. Moreover, POLA2 was also positively co-expressed with some immune checkpoints (CD274, CTL-4, HAVCR2, PDCD1, PDCD1LG2, TIGIT, and LAG3) (p < 0.001). Gene knockdown revealed that POLA2 promoted proliferation, migration, invasion, and cell cycle of SMMC-7721 and HepG2. The HCC xenograft tumor model also demonstrated remarkably tumor size inhibition, tumor proliferation inhibtion and tumor necrosis promotion when POLA2 knockdown.ConclusionsPOLA2 influenced immune microenvironment and tumor progression of HCC indicated that it might be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.

CBP60‐DB: An AlphaFold‐predicted plant kingdom‐wide database of the CALMODULIN‐BINDING PROTEIN 60 protein family with a novel structural clustering algorithm

AbstractMolecular genetic analyses in the model species Arabidopsis thaliana have demonstrated the major roles of different CALMODULIN‐BINDING PROTEIN 60 (CBP60) proteins in growth, stress signaling, and immune responses. Prominently, CBP60g and SARD1 are paralogous CBP60 transcription factors that regulate numerous components of the immune system, such as cell surface and intracellular immune receptors, MAP kinases, WRKY transcription factors, and biosynthetic enzymes for immunity‐activating metabolites salicylic acid (SA) and N‐hydroxypipecolic acid (NHP). However, their function, regulation, and diversification in most species remain unclear. Here, we have created CBP60‐DB (https://cbp60db.wlu.ca/), a structural and bioinformatic database that comprehensively characterized 1052 CBP60 gene homologs (encoding 2376 unique transcripts and 1996 unique proteins) across 62 phylogenetically diverse genomes in the plant kingdom. We have employed deep learning‐predicted structural analyses using AlphaFold2 and then generated dedicated web pages for all plant CBP60 proteins. Importantly, we have generated a novel clustering visualization algorithm to interrogate kingdom‐wide structural similarities for more efficient inference of conserved functions across various plant taxa. Because well‐characterized CBP60 proteins in Arabidopsis are known to be transcription factors with putative calmodulin‐binding domains, we have integrated external bioinformatic resources to analyze protein domains and motifs. Collectively, we present a plant kingdom‐wide identification of this important protein family in a user‐friendly AlphaFold‐anchored database, representing a novel and significant resource for the broader plant biology community.

Beyond the genomes of Fulvia fulva (syn. Cladosporium fulvum) and Dothistroma septosporum: New insights into how these fungal pathogens interact with their host plants.

Fulvia fulva and Dothistroma septosporum are closely related apoplastic pathogens with similar lifestyles but different hosts: F.fulva is a pathogen of tomato, whilst D.septosporum is a pathogen of pine trees. In 2012, the first genome sequences of these pathogens were published, with F.fulva and D.septosporum having highly fragmented and near-complete assemblies, respectively. Since then, significant advances have been made in unravelling their genome architectures. For instance, the genome of F.fulva has now been assembled into 14 chromosomes, 13 of which have synteny with the 14 chromosomes of D.septosporum, suggesting these pathogens are even more closely related than originally thought. Considerable advances have also been made in the identification and functional characterization of virulence factors (e.g., effector proteins and secondary metabolites) from these pathogens, thereby providing new insights into how they promote host colonization or activate plant defence responses. For example, it has now been established that effector proteins from both F.fulva and D.septosporum interact with cell-surface immune receptors and co-receptors to activate the plant immune system. Progress has also been made in understanding how F.fulva and D.septosporum have evolved with their host plants, whilst intensive research into pandemics of Dothistroma needle blight in the Northern Hemisphere has shed light on the origins, migration, and genetic diversity of the global D.septosporum population. In this review, we specifically summarize advances made in our understanding of the F.fulva-tomato and D.septosporum-pine pathosystems over the last 10 years.

Conservation of the PBL-RBOH immune module in land plants

The rapid production of reactive oxygen species (ROS) is a key signaling output in plant immunity. In the angiosperm model species Arabidopsis thaliana (hereafter Arabidopsis), recognition of non- or altered-self elicitor patterns by cell-surface immune receptors activates the receptor-like cytoplasmic kinases (RLCKs) of the AVRPPHB SUSCEPTIBLE 1 (PBS1)-like (PBL) family, particularly BOTRYTIS-INDUCED KINASE1 (BIK1).1,2,3 BIK1/PBLs in turn phosphorylate the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) to induce apoplastic ROS production.4,5 PBL and RBOH functions in plant immunity have been extensively characterized in flowering plants. Much less is known about the conservation of pattern-triggered ROS signaling pathways in non-flowering plants. In this study, we show that in the liverwort Marchantia polymorpha (hereafter Marchantia), single members of the RBOH and PBL families, namely MpRBOH1 and MpPBLa, are required for chitin-induced ROS production. MpPBLa directly interacts with and phosphorylates MpRBOH1 at specific, conserved sites within its cytosolic N terminus, and this phosphorylation is essential for chitin-induced MpRBOH1-mediated ROS production. Collectively, our work reveals the functional conservation of the PBL-RBOH module that controls pattern-triggered ROS production in land plants.

CD200R1 promotes interleukin-17 production by group 3 innate lymphoid cells by enhancing signal transducer and activator of transcription 3 activation

Psoriasis is a common chronic inflammatory skin disease with no cure. It is driven by the interleukin (IL)-23/IL-17A axis and type 17 T helper cells; however, recently, group 3 innate lymphoid cells (ILC3s) have also been implicated. Despite being the focus of much research, factors regulating the activity of ILC3s remain incompletely understood. Immune regulatory pathways are particularly important at barrier sites, such as the skin, gut, and lungs, which are exposed to environmental substances and microbes. CD200R1 is an immune regulatory cell surface receptor that inhibits proinflammatory cytokine production in myeloid cells. CD200R1 is also highly expressed on ILCs, where its function remains largely unexplored. We previously observed reduced CD200R1 signaling in psoriasis-affected skin, suggesting that dysregulation may promote disease. Here, we show that contrary to this, psoriasis models are less severe in CD200R1-deficient mice due to reduced IL-17 production. Here, we uncover a key cell-intrinsic role for CD200R1 in promoting IL-23-driven IL-17A production by ILC3s by promoting signal transducer and activator of transcription 3 activation. Therefore, contrary to its inhibitory role in myeloid cells, CD200R1 is required on ILC3 to promote IL-23-stimulated signal transducer and activator of transcription 3 activation, triggering optimal IL-17 production.

LilrB3 is a putative cell surface receptor of APOE4.

The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE isoform dependence remains enigmatic. Here we demonstrate that APOE4, but not APOE2, specifically interacts with the leukocyte immunoglobulin-like receptor B3 (LilrB3). Two discrete immunoglobin-like domains of the LilrB3 extracellular domain (ECD) recognize a positively charged surface patch on the N-terminal domain (NTD) of APOE4. The atomic structure reveals how two APOE4 molecules specifically engage two LilrB3 molecules, bringing their intracellular signaling motifs into close proximity through formation of a hetero-tetrameric complex. Consistent with our biochemical and structural analyses, APOE4, but not APOE2, activates human microglia cells (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. Together, our study identifies LilrB3 as a putative immune cell surface receptor for APOE4, but not APOE2, and may have implications for understanding the biological functions as well as disease relevance of the APOE isoforms.

CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation.

Multiple myeloma (MM) is an incurable plasma cell malignancy, while CAR-T therapy offers a new direction for the treatment of MM. Recently, signaling lymphocytic activation molecule family 3 (CD229), a cell surface immune receptor belonging to the signaling lymphocyte activating molecule family (SLAMF), is emerging as a CAR-T therapeutic target in MM. However, a clear role of CD229 in MM remains elusive. In this study, MM patients with elevated CD229 expression achieved poor prognosis by analyzing MM clinical databases. In addition, CD229 promoted MM cell proliferation in vitro as well as in xenograft mouse model in vivo. Mechanism study revealed that CD229 promoted MM cell proliferation by regulating the RAS/ERK signaling pathway. Further exploration employed co-immunoprecipitation coupled with mass spectrometry to identify RASAL3 as an important downstream protein of CD229. Additionally, we developed a co-culture method combined with the immunofluorescence assay to confirm that intercellular tyrosine phosphorylation mediated self-activation of CD229 to activate RAS/ERK signaling pathway via interacting with RASAL3. Taken together, these findings not only demonstrate the oncogenic role of CD229 in MM cell proliferation, but also illustrate the potential of CD229 as a promising therapeutic target for MM treatment.

Concerted actions of PRR- and NLR-mediated immunity.

Plants utilise cell-surface immune receptors (functioning as pattern recognition receptors, PRRs) and intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) to detect pathogens. Perception of pathogens by these receptors activates immune signalling and resistance to infections. PRR- and NLR-mediated immunity have primarily been considered parallel processes contributing to disease resistance. Recent studies suggest that these two pathways are interdependent and converge at multiple nodes. This review summarises and provides a perspective on these convergent points.

742P First-in-human phase I study of INCAGN02385, a LAG-3 monoclonal antibody antagonist in patients with advanced malignancies

Lymphocyte activation gene 3 (LAG-3) is a cell-surface immune checkpoint receptor that negatively regulates cell activation and proliferation. INCAGN02385 is a humanized Fc-engineered IgG1κ monoclonal antibody with selective and potent LAG-3 antagonist action against LAG-3 binding to MHC class II, leading to enhanced TCR signaling and cytokine secretion of activated T cells. This study primarily aims to determine safety and tolerability and define the MTD or PAD of INCAGN02385 monotherapy.

β-Glucan-Functionalized Nanoparticles Down-Modulate the Proinflammatory Response of Mononuclear Phagocytes Challenged with Candida albicans.

Systemic fungal infections are associated with significant morbidity and mortality, and Candida albicans is the most common causative agent. Recognition of yeast cells by immune cell surface receptors can trigger phagocytosis of fungal pathogens and a pro-inflammatory response that may contribute to fungal elimination. Nevertheless, the elicited inflammatory response may be deleterious to the host by causing excessive tissue damage. We developed a nanoparticle-based approach to modulate the host deleterious inflammatory consequences of fungal infection by using β1,3-glucan-functionalized polystyrene (β-Glc-PS) nanoparticles. β-Glc-PS nanoparticles decreased the levels of the proinflammatory cytokines TNF-α, IL-6, IL-1β and IL-12p40 detected in in vitro culture supernatants of bone marrow-derived dendritic cells and macrophage challenged with C. albicans cells. Moreover, β-Glc-PS nanoparticles impaired the production of reactive oxygen species by bone marrow-derived dendritic cells incubated with C. albicans. This immunomodulatory effect was dependent on the nanoparticle size. Overall, β-Glc-PS nanoparticles reduced the proinflammatory response elicited by fungal cells in mononuclear phagocytes, setting the basis for a targeted therapy aimed at protecting the host by lowering the inflammatory cost of infection.

β-Glucan: Mode of Action and Its Uses in Fish Immunomodulation

β-glucan is considered as an effective immunostimulant because of its binding capacity to different receptors on leukocytes leading to the stimulation of immune responses including bactericidal activity, cytokine productivity, and survival fit ability at cellular levels. In response to immune cell surface receptors, β-glucan stimulates to release cytokines and chemokines. It has been found that these signaling proteins eventually stimulate the immunocompetent cells in fish such as monocytes, macrophages, and neutrophils for killing pathogens by phagocytosis, oxidative burst, and cytotoxic killing activities. They also procreate immunological memories and specific antibodies through activation of T and B lymphocytes. Researchers have proved that β-glucan can modulate some important biochemical (serum hemoglobin, serum protein, and total hemocyte count) and immunological (lysozyme activity, phagocytic activity, oxidative burst activity, and phenoloxidase activity) properties providing more competent immune profile for treating fish and aquatic organisms. β-glucan-supplemented fish showed limited sensitivity of genes involved in acute inflammatory reactions. Findings have shown that β-glucan exerts a positive impact on fish and aquatic organisms’ immunity, enhancing their disease resistance by increasing functional and decreasing deleterious responses. This review focuses on the basic bump of β-glucan on fish and shellfish immunity and recent information on the uses of β-glucan in progressive aquaculture.