Innate Function Research Articles

Trained immunity in the pathogenesis of vitiligo.

Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system-through cytotoxic CD8+ T cells and melanocyte specific antibodies-and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long-term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis.

NLRP3 agonist enhances radiation-induced immune priming and promotes abscopal responses in anti-PD1 resistant model.

Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.

A Panorama of Immune Fighters Armored with CARs in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging option. Ultimately, a subset of patients will relapse or have refractory disease, posing a huge challenge to further therapeutic decisions. Targeted immunotherapies hold promise for relapsed/refractory (r/r) malignancies by directing the immune system against cancer. Chimeric antigen receptors (CARs) are important components of targeted immunotherapy. Indeed, CAR-T cells have achieved unprecedented success against r/r CD19+ malignancies. However, CAR-T cells have only achieved modest outcomes in clinical studies on r/r AML. Natural killer (NK) cells have innate anti-AML functionality and can be engineered with CARs to improve their antitumor response. CAR-NKs are associated with lower toxicities than CAR-T cells; however, their clinical efficacy against AML has not been extensively investigated. In this review, we cite the results from clinical studies of CAR-T cells in AML and describe their limitations and safety concerns. Moreover, we depict the clinical and preclinical landscape of CAR used in alternative immune cell platforms with a specific focus on CAR-NKs, providing insight into the future optimization of AML.

Expression in popular music singing as embodied and interpersonal

This article presents theoretical viewpoints for considering and understanding expression in popular music singing and pedagogy from the perspective of embodiment as outlined in Merleau-Ponty’s phenomenological philosophy. In our study, we apply his interpretations of such notions as intentionality, body schema, gesture, reversibility, and intersubjectivity to bring forth and discuss the holistic, embodied, and interpersonal nature of voice expression in singing. We argue that expression should be viewed as an intentional activity, based on the body’s innate mindful functioning as a whole, and in singing guided by the lyrics and emotions to be communicated. We propose that this requires a “free voice”, based on healthy vocal production, that also allows for the immediacy of expression as and through gestures that bring the meaning into existence. We further argue that expression is an interpersonal, interactive, and intersubjective process in which the performer and listener influence each other in many ways. The reversibility of perception in expression means that perception and the object perceived are intertwined and action and perception are interconnected. There is also a gap in reversibility, which implies that the perception of (one’s own) expression is never complete. In addition to our theoretical arguments, we make pedagogical suggestions, such as that the body itself has a lot of understanding ofhowand should be trusted in singing, both in terms of voice production and expression. The expression should not be primarily approached as a technical issue but taught in connection with and through expression. The expression should be viewedfrom the inside out, not the opposite. This means that expression builds on one’s personality and (emotional) experiences.

Genetically Engineered Artificial Exosome-Constructed Hydrogel for Ovarian Cancer Therapy.

Owing to the insidious onset of ovarian cancer, most patients are in the advanced stage with extensive peritoneal metastasis when they are diagnosed. Treatment of peritoneal metastasis from advanced ovarian cancer remains a significant challenge. Inspired by the massive macrophages in the peritoneal environment, here, we reported an artificial exosome-based peritoneal-localized hydrogel to domesticate peritoneal macrophages as the therapeutic target for realizing potent ovarian cancer therapy, where artificial exosomes derived from genetically sialic-acid-binding Ig-like lectin 10 (Siglec-10)-engineered M1-type macrophages were chemically designed as gelator. Upon triggering immunogenicity with X-ray radiation, our hydrogel encapsulating efferocytosis inhibitor MRX-2843 enabled a cascade regulation to orchestrate polarization, efferocytosis, and phagocytosis of peritoneal macrophages for realizing robust phagocytosis of tumor cells and powerful antigen presentation, offering a potent approach for ovarian cancer therapy via bridging the innate effector function of macrophages with their adaptive immune response. Moreover, our hydrogel is also applicable for potent treatment of inherent CD24-overexpressed triple-negative breast cancer, providing an emerging therapeutic regimen for the most lethal malignancies in women.

DANGER Signals Activate G -Protein Receptor Kinases Suppressing Neutrophil Function and Predisposing to Infection After Tissue Trauma.

Injured tissue predisposes the subject to local and systemic infection. We studied injury-induced immune dysfunction seeking novel means to reverse such predisposition. Injury mobilizes primitive "DANGER signals" [danger-associated molecular patterns (DAMPs)] activating innate immunocyte (neutrophils, PMN) signaling and function. Mitochondrial formyl peptides activate G -protein coupled receptors (GPCR) like formyl peptide receptor-1. Mitochondrial DNA and heme activate toll-like receptors (TLR9 and TLR2/4). GPCR kinases (GRKs) can regulate GPCR activation. We studied human and mouse PMN signaling elicited by mitochondrial DAMPs (GPCR surface expression; protein phosphorylation, or acetylation; Ca 2+ flux) and antimicrobial functions [cytoskeletal reorganization, chemotaxis (CTX), phagocytosis, bacterial killing] in cellular systems and clinical injury samples. Predicted rescue therapies were assessed in cell systems and mouse injury-dependent pneumonia models. Mitochondrial formyl peptides activate GRK2, internalizing GPCRs and suppressing CTX. Mitochondrial DNA suppresses CTX, phagocytosis, and killing through TLR9 through a novel noncanonical mechanism that lacks GPCR endocytosis. Heme also activates GRK2. GRK2 inhibitors like paroxetine restore functions. GRK2 activation through TLR9 prevented actin reorganization, implicating histone deacetylases (HDACs). Actin polymerization, CTX, bacterial phagocytosis, and killing were also rescued, therefore, by the HDAC inhibitor valproate. Trauma repository PMN showed GRK2 activation and cortactin deacetylation, which varied with severity and was most marked in patients developing infections. Either GRK2 or HDAC inhibition prevented loss of mouse lung bacterial clearance, but only the combination rescued clearance when given postinjury. Tissue injury-derived DAMPs suppress antimicrobial immunity through canonical GRK2 activation and a novel TLR-activated GRK2-pathway impairing cytoskeletal organization. Simultaneous GRK2/HDAC inhibition rescues susceptibility to infection after tissue injury.

Plasma Derived Extracellular Vesicles Modulate Monocyte IL-18, IFN-α and IL-10 responses in Adults with HIV-related Cognitive Impairment

Abstract Background: HIV-associated neurocognitive dysfunction persists despite suppressive antiretroviral therapy (ART). Extracellular vesicles (EVs) are emerging modulators of immunological responses. We have previously shown that EVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment (CI). Whether these EV changes observed in people with HIV (PWH) influence innate cellular function among those with CI remains unclear. Method: Purified EV samples from 58 HIV-infected individuals on ART with either cognitive impairment (CI, n=48) or normal cognition (NC, n=10) and 8 uninfected controls were isolated using differential centrifugation and co-cultured with PBMCs from a single uninfected donor for 18 hrs. Eight intracellular cytokines and 13 surface chemokines and myeloid differentiation markers were assessed by spectral flow cytometry. Non-parametric statistical T tests were used. Result: Monocytes (mono) showed differential effects on multiple cytokine responses and cell surface receptors after exposure to EVs from HIV-infected individuals with or without CI. Levels of mono IL-18 were significantly lower after incubation with EVs derived from HIV-infected individuals compared to uninfected controls. Based on cognitive status, EVs from HIV-CI group significantly lower % of IL-18 mono responses and lower IFN-α and higher IL-10 responses on a per cell basis when compared to the NC group. Conclusion: These results suggest EVs can modulate mono function irrespective of HIV status. PWH with CI exhibited altered EV driven mono cytokine responses. Our data support interventions that target EVs to reverse or restore mono perturbations and limit neuropathology in PWH on ART. Supported by grants from NIH (R21NS106970 and R01NS117458)

C-Kit signaling modulated group 3 innate lymphoid cell functions in mouse neutrophilic asthma model

Abstract Group 3 innate lymphoid cells (ILC3s) are involved in air pollution- and bacterial infection-associated neutrophilic asthma. Studies showed that asthmatic patients have higher stem cell factor (SCF) expression in airway and sera. Of note, ILC3s express SCF receptor, c-Kit, suggesting a potential role of SCF/c-Kit signaling in ILC3 functions and neutrophilic asthma. In this study, we aimed to determine whether SCF/c-Kit signaling could modulate ILC3 functions and neutrophilic asthma. Wild-type (WT) and c-Kit deficient mice (Kit w-sh) were intranasally treated with IL-1β/IL-23 or particulate matter (PM) 2.5 to induce neutrophilic asthma. While IL-1β/IL-23 or PM2.5 caused increases in neutrophil infiltration to bronchoalveolar lavage fluid (BALF) and airway hyperreactivity (AHR) in WT mice, Kit w-shmice had decreased infiltration of neutrophils and ameliorated AHR. Concomitantly, flow cytometry results showed a decreased number of IL-17+ ILC3 in the lung of Kit w-shmice compared to WT mice, which may be due to the reduced proliferation of c-Kit-deficient ILC3. In addition, we showed SCF enhanced IL-17 secretion from ILC3s in vitro. Based on re-analysis of published mouse whole lung cells scRNAseq data, we hypothesized fibroblasts are the source of SCF. Indeed, mice with SCF knockout in fibroblast exhibited decreased neutrophil infiltration and reduced IL-17+ ILC3 number in response to IL-1β/IL-23. Finally, administration of imatinib, a FDA-approved drug targeting c-Kit signaling, ameliorated AHR and ILC3 activation in the mouse neutrophilic asthma model. Taken together, our data suggested that inhibition of ILC3 activation by targeting c-Kit signaling may provide a potential therapeutic management for neutrophilic asthma.

Senescent CD8+ T cells acquire NK cell-like innate functions to promote antitumor immunity.

It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8+ T cells. Furthermore, Menin-deficient CD8+ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.

A Conformable Ultrasound Patch for Cavitation-Enhanced Transdermal Cosmeceutical Delivery.

Increased consumer interest in healthy-looking skin demands a safe and effective method to increase transdermal absorption of innovative therapeutic cosmeceuticals. However, permeation of small-molecule drugs is limited by the innate barrier function of the stratum corneum. Here, a conformable ultrasound patch (cUSP) that enhances transdermal transport of niacinamide by inducing intermediate-frequency sonophoresis in the fluid coupling medium between the patch and the skin is reported. The cUSP consists of piezoelectric transducers embedded in a soft elastomer to create localized cavitation pockets (0.8 cm2 , 1mm deep) over larger areas of conformal contact (20 cm2 ). Multiphysics simulation models, acoustic spectrum analysis, and high-speed videography are used to characterize transducer deflection, acoustic pressure fields, and resulting cavitation bubble dynamics in the coupling medium. The final system demonstrates a 26.2-fold enhancement in niacinamide transport in a porcine model in vitro with a 10 min ultrasound application, demonstrating the suitability of the device for short-exposure, large-area application of sonophoresis for patients and consumers suffering from skin conditions and premature skin aging.

Bioempowerment of Therapeutic Living Cells by Single‐Cell Surface Engineering

AbstractLiving cells have the irreplaceable capability to achieve a wide range of complex biochemical reactions precisely and efficiently, which makes them attractive materials for therapeutic applications. In lieu of the traditional biochemical and biological approaches primarily focused on the augmentation of the innate functions of cells, there has been appreciable progress in the development of engineered therapeutic cells, mainly based on the chemical modifications of cell surfaces, at the single‐cell level, which empowers individual living cells with designed therapeutic functions in a cytocompatible manner. This review highlights the latest advances in the development of therapeutic living cells using single‐cell surface engineering, for potential applications in blood transfusion, drug delivery, cancer therapy, probiotic therapy, and tissue engineering and regenerative medicine. The methodological strategies for functionalizing cell surfaces with biomolecules, and inorganic and organic materials, to endow living cells with extrinsic physicochemical and biological properties as well as to increase the durability and efficacy of engineered therapeutic cells, are also briefly overviewed. The review ends with a perspective that discusses the construction of active cell‐in‐shell nanobiohybrid systems, in which exogenous materials formed on cell surfaces mutually and intimately communicate with the cells inside, as a future research direction for single‐cell surface engineering.

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3

Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs. Further analyses identified EhaF as a secreted autotransporter—a type of bacterial secretion system with no known innate immune-modulatory function—that translocates into host cell cytosol and inhibit IFN response to EHEC. Mechanistically, EhaF interacts with and inhibits the MiT/TFE family transcription factor TFE3 resulting in impaired TANK phosphorylation and consequently, reduced IRF3 activation and type I IFN expression. Notably, EhaF-mediated innate immune suppression promotes EHEC colonization and pathogenesis in vivo. Overall, this study has uncovered a previously unknown autotransporter-based bacterial strategy that targets a specific transcription factor to subvert innate host defense.

Quest for a Rational Molecular Design of Alkyl-Distyrylbenzene Liquid by Substitution Pattern Modulation.

Alkyl-π functional molecular liquids (FMLs) are of interest for fabricating soft electronic devices due to their fluidic nature and innate optoelectronic functions from the π-conjugated moiety. However, predictable development of alkyl-π FMLs with the desired liquid and optoelectronic properties is challenging. A series of alkyl-distyrylbenzene (DSB) liquids was studied in terms of the substituent position effect by attaching 2-octyldodecyl chains at (2,4-), (2,5-), (2,6-), and (3,5-). The effect of the alkyl chain length was investigated by attaching 2-hexyldecyl, 2-decyltetradecyl (C10 C14 ), and 2-dodecylhexadecyl at the (2,5-) substituent position. The 2,5-C10 C14 substituent pattern constructed a superior alkyl-DSB liquid with a lower viscosity, intrinsic optical properties, and high thermal- and photo-stabilities. The discovered 2,5-C10 C14 was applied to dicyanostyrylbenzene and comparable liquid physical and optical superiorities were confirmed. This molecular design is useful for creating alkyl-π FMLs with the aforementioned advantages, which are applicable for deformable and flowable optoelectronic devices.

Maternal γδ Tcells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.

Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ Tcell-deficient (TCRδ-/-) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ Tcell-sufficient dams. Upon helminth infection, mice born from TCRδ-/- dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ-/- dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ Tcell-microbiota-SCFA axis regulating neonatal lung immunity.

Advances in Escherichia coli Nissle 1917 as a customizable drug delivery system for disease treatment and diagnosis strategies.

With the in-depth and comprehensive study of bacteria and their related ecosystems in the human body, bacterial-based drug delivery system has become an emerging biomimetic platform that can retain the innate biological functions. Benefiting from its good biocompatibility and ideal targeting ability as a biological carrier, Escherichia coli Nissle 1917 (ECN) has been focused on the treatment strategies of inflammatory bowel disease and tumor. The advantage of a bacterial carrier is that it can express exogenous protein while also acting as a natural capsule by releasing drug slowly as a result of its own colonization impact. In order to survive in harsh environments such as the digestive tract and tumor microenvironment, ECN can be modified or genetically engineered to enhance its function and host adaptability. The adoption of ECN carries or expresses drugs which are essential for accurate diagnosis and treatment. This review briefly describes the properties of ECN, the relationship between ECN and inflammation and tumor, and the strategy of using surface modification and genetic engineering to modify ECN as a delivery carrier for disease treatment.

3D bioprinting-a model for skin aging.

Human lifespan continues to extend as an unprecedented number of people reach their seventh and eighth decades of life, unveiling chronic conditions that affect the older adult. Age-related skin conditions include senile purpura, seborrheic keratoses, pemphigus vulgaris, bullous pemphigoid, diabetic foot wounds and skin cancer. Current methods of drug testing prior to clinical trials require the use of pre-clinical animal models, which are often unable to adequately replicate human skin response. Therefore, a reliable model for aged human skin is needed. The current challenges in developing an aged human skin model include the intrinsic variability in skin architecture from person to person. An ideal skin model would incorporate innate functionality such as sensation, vascularization and regeneration. The advent of 3D bioprinting allows us to create human skin equivalent for use as clinical-grade surgical graft, for drug testing and other needs. In this review, we describe the process of human skin aging and outline the steps to create an aged skin model with 3D bioprinting using skin cells (i.e. keratinocytes, fibroblasts and melanocytes). We also provide an overview of current bioprinted skin models, associated limitations and direction for future research.

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Influenza A Virus: Cellular Entry.

The frequent emergence of pathogenic viruses with pandemic potential has posed a significant threat to human health and economy, despite enormous advances in our understanding of infection mechanisms and devising countermeasures through developing various prophylactic and therapeutic strategies. The recent coronavirus disease (COVID-19) pandemic has re-emphasised the importance of rigorous research on virus infection mechanisms and highlighted the need for our preparedness for potential pandemics. Although viruses cannot self-replicate, they tap into host cell factors and processes for their entry, propagation and dissemination. Upon entering thehost cells, viruses ingeniously utilise the innate biological functions of the host cell to replicate themselves and maintain their existencein the hosts. Influenza A virus (IAV), which has a negative-sense, single-stranded RNA as its genome, is no exception. IAVs are enveloped viruses with a lipid bilayer derived from the host cell membrane and have a surface covered with the spike glycoprotein haemagglutinin (HA) and neuraminidase (NA). Viral genome is surrounded by an M1 shell, forming a "capsid" in the virus particle. IAV particles use HA to recognise sialic acids on the cell surface of lung epithelial cells for their attachment. After attachment to the cell surface, IAV particles areendocytosed and sorted into the earlyendosomes. Subsequently, as the earlyendosomes matureinto late endosomes, the endosomal lumen becomes acidified, andthe low pH of the lateendosomes induces conformational reaggangements in theHA toinitiate fusion between the endosomal and viral membranes. Upon fusion, the viral capsid disintegrates and the viral ribonucleoprotein (vRNP) complexescontaining the viral genome are released into the cytosol. The process of viral capsid disintegration is called "uncoating". After successful uncoating, the vRNPs are imported into the nucleus byimportin α/β (IMP α/β), where viral replication and transcription take placeand thenew vRNPs are assembled. Recently, we have biochemically elucidated the molecular mechanisms of the processes ofviral capsid uncoating subsequent viral genome dissociation. In this chapter,we present the moleculardetails of the viraluncoating process.

Nipocalimab’s Selective Targeting of FcRn and IgG Clearance Preserves Key Immune Functions

Objective To characterize the effect of nipocalimab, a fully human, effectorless IgG1 anti-neonatal Fc receptor (FcRn) monoclonal antibody on immune function. Background Nipocalimab binds to FcRn with high affinity which prevents IgG recycling, leading to reduced serum levels of total IgGs, including pathogenic IgG autoantibodies. Rapid, sustained lowering of IgG was observed in the phase 2 VIVACITY study in generalized myasthenia gravis (gMG) and in phase 1 healthy volunteers. In gMG patients, nipocalimab induced rapid and sustained lowering of anti-AChR autoantibodies and MG-ADL scores, but no serious adverse events including clinically significant infections. Design/Methods Nipocalimab was evaluated extensively in vitro and in nonhuman primate-based chronic toxicology studies to evaluate selectivity, tolerability, safety and immunopharmacology. Safety, tolerability and immune-focused assessments in clinical phase 1 and Phase 2 MG studies were also completed (NCT02828046, NCT03772587). Results Nipocalimab binds specifically in vitro to FcRn without activation of effector function or inhibition of antigen presentation. In nonhuman primates administered up to 300 mg/kg nipocalimab QW for up to 6 months, sustained lowering of IgG was observed without adverse effects. Immunotoxicology identified no effect on immune cell phenotypes; CD8 T cell, NK or innate cell functions; T-dependent neoantigen IgM responses. Neoantigen IgG production was observed, but with lowered peak IgG titers consistent with the anticipated increase in IgG clearance with nipocalimab. In clinical studies, nipocalimab demonstrated a reproducible selective decrease in total serum IgG, including all subclasses of IgG, with no effect on IgM, IgA, IgE, CH50, C3, C4, inflammatory cytokines or acute phase proteins including, C-reactive protein (CRP). Conclusions These data suggest that nipocalimab can selectively lower IgG and IgG autoantibodies while preserving cellular immunity, complete IgM response and IgG production after neoantigen challenge. Overall, nipocalimab's selective effect on IgG recycling provides a mechanistic rationale for potentially decreased infection risk despite substantial IgG lowering.

STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.

STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authorsreport that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.