Host Immune Cells Research Articles

Candida albicans pathways that protect against organic peroxides and lipid peroxidation.

Human fungal pathogens must survive diverse reactive oxygen species (ROS) produced by host immune cells that can oxidize a range of cellular molecules including proteins, lipids, and DNA. Formation of lipid radicals can be especially damaging, as it leads to a chain reaction of lipid peroxidation that causes widespread damage to the plasma membrane. Most previous studies on antioxidant pathways in fungal pathogens have been conducted with hydrogen peroxide, so the pathways used to combat organic peroxides and lipid peroxidation are not well understood. The most well-known peroxidase in Candida albicans, catalase, can only act on hydrogen peroxide. We therefore characterized a family of four glutathione peroxidases (GPxs) that were predicted to play an important role in reducing organic peroxides. One of the GPxs, Gpx3 is also known to activate the Cap1 transcription factor that plays the major role in inducing antioxidant genes in response to ROS. Surprisingly, we found that the only measurable role of the GPxs is activation of Cap1 and did not find a significant role for GPxs in the direct detoxification of peroxides. Furthermore, a CAP1 deletion mutant strain was highly sensitive to organic peroxides and oxidized lipids, indicating an important role for antioxidant genes upregulated by Cap1 in protecting cells from organic peroxides. We identified GLR1 (Glutathione reductase), a gene upregulated by Cap1, as important for protecting cells from oxidized lipids, implicating glutathione utilizing enzymes in the protection against lipid peroxidation. Furthermore, an RNA-sequencing study in C. albicans showed upregulation of a diverse set of antioxidant genes and protein damage pathways in response to organic peroxides. Overall, our results identify novel mechanisms by which C. albicans responds to oxidative stress resistance which open new avenues for understanding how fungal pathogens resist ROS in the host.

Oral Pathobiont-Derived Outer Membrane Vesicles in the Oral–Gut Axis

Oral pathobionts are essential in instigating local inflammation within the oral cavity and contribute to the pathogenesis of diseases in the gastrointestinal tract and other distant organs. Among the Gram-negative pathobionts, Porphyromonas gingivalis and Fusobacterium nucleatum emerge as critical drivers of periodontitis, exerting their influence not only locally but also as inducers of gut dysbiosis, intestinal disturbances, and systemic ailments. This dual impact is facilitated by their ectopic colonization of the intestinal mucosa and the subsequent mediation of distal systemic effects by releasing outer membrane vesicles (OMVs) into circulation. This review elucidates the principal components of oral pathobiont-derived OMVs implicated in disease pathogenesis within the oral–gut axis, detailing virulence factors that OMVs carry and their interactions with host epithelial and immune cells, both in vitro and in vivo. Additionally, we shed light on the less acknowledged interplay between oral pathobionts and the gut commensal Akkermansia muciniphila, which can directly impede oral pathobionts’ growth and modulate bacterial gene expression. Notably, OMVs derived from A. muciniphila emerge as promoters of anti-inflammatory effects within the gastrointestinal and distant tissues. Consequently, we explore the potential of A. muciniphila-derived OMVs to interact with oral pathobionts and prevent disease in the oral–gut axis.

Exploring the Probiotic Potential of Bacteroides spp. Within One Health Paradigm.

Probiotics are pivotal in maintaining or restoring the balance of human intestinal microbiota, a crucial factor in mitigating diseases and preserving the host's health. Exploration into Bacteroides spp. reveals substantial promise in their development as next-generation probiotics due to their profound interaction with host immune cells and capability to regulate the microbiome's metabolism by significantly impacting metabolite production. These beneficial bacteria exhibit potential in ameliorating various health issues such as intestinal disorders, cardiovascular diseases, behavioral disorders, and even cancer. Though it's important to note that a high percentage of them are as well opportunistic pathogens, posing risks under certain conditions. Studies highlight their role in modifying immune responses and improving health conditions by regulating lymphocytes, controlling metabolism, and preventing inflammation and cancer. The safety and efficacy of Bacteroides strains are currently under scrutiny by the European Commission for authorization in food processing, marking a significant step towards their commercialization. The recent advancements in bacterial isolation and sequencing methodologies, coupled with the integration of Metagenome-Assembled Genomes (MAGs) binning from metagenomics data, continue to unveil the potential of Bacteroides spp., aiding in the broader understanding and application of these novel probiotics in health and disease management.

Tumor-derived Exosomes and Antitumor Immunity.

Cancer immunotherapy, including immune checkpoint blockade, has been approved for treatment of patients with many cancer types. However, some patients fail to respond to immunotherapy, and emerging evidence indicates that tumor-derived exosomes (TEX) play a major role in reprogramming the host immune cells by inducing their dysfunction. Focusing on effector T cells, this review illustrates mechanisms of suppression that TEX use, thus promoting tumor escape from the host immune system. TEX carry multiple suppressive signals that drive T cell dysfunction and convert the tumor microenvironment into "an immune desert" in which activated T cells either die or are reprogrammed to mediate protumor functions. The reprogrammed T cells produce a new crop of CD3+ immunoinhibitory exosomes that further amplify suppression mediated by TEX. The result is a profound depletion of antitumor immune effector cells that reflects the defective immune competence of the cancer patient and partly explains why TEX are a significant barrier for cancer immunotherapy.

Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica

ABSTRACT Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host’s immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the activation and regulation of immune cells is essential to understanding host immunity and immune-related pathology. It is also important to comprehend how pathogens secrete specific ncRNAs to manipulate gene expression of host immune cells and influence their response to infection. To investigate the contribution of both host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during a parasite infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with Fasciola hepatica. We discovered the presence of several parasitic-derived miRNAs within host macrophages at 6 hrs and 18 hrs post infection. Target prediction analysis showed that these Fasciola miRNAs regulate host genes associated with the activation of host pro-inflammatory macrophages. Concomitantly, there was a distinct shift in host ncRNA expression, which was significant at 5 days post-infection. Prediction analysis suggested that these host ncRNAs target a different cohort of host genes compared to the parasite miRNAs, although the functional outcome was predicted to be similar i.e. reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Taken together, these observations uncover the interplay between host and parasitic ncRNAs and reveal a complementary regulation of the immune response that allows the parasite to evade immune detection and promote tissue repair for the host. These findings will provide a new understanding of the molecular interaction between parasites and host.

A Study of Disease Prognosis in Lung Adenocarcinoma Using Single-Cell Decomposition and Immune Signature Analysis.

Background: The development of tumors is a highly complex process that entails numerous interactions and intricate relationships between the host immune system and cancer cells. It has been demonstrated in studies that the treatment response of patients can be correlated with the tumor microenvironment (TME). Consequently, the examination of diverse immune profiles within the TME can facilitate the elucidation of tumor development and the development of advantageous models for diagnoses and prognoses. Methods: In this study, we utilized a single-cell decomposition method to analyze the relationships between cell proportions and immune signatures in lung adenocarcinoma (LUAD) patients. Results: Our findings indicate that specific immune cell populations and immune signatures are significantly associated with patient prognosis. By identifying poor prognosis signatures (PPS), we reveal the critical role of immune profiles and cellular composition in disease outcomes, emphasizing their diagnostic potential for predicting patient prognosis. Conclusions: This study highlights the importance of immune signatures and cellular composition, which may serve as valuable biomarkers for disease prognosis in LUAD patients.

Effect of Staphylococcus aureus colonization and immune defects on the pathogenesis of atopic dermatitis.

Atopic dermatitis (AD) is a common and recurrent skin disease characterized by skin barrier dysfunction, inflammation and chronic pruritus, with wide heterogeneity in terms of age of onset, clinical course and persistence over the lifespan. Although the pathogenesis of the disease are unclear, epidermal barrier dysfunction, immune and microbial dysregulation, and environmental factors are known to be critical etiologies in AD pathology. The skin microbiota represents an ecosystem consisting of numerous microbial species that interact with each other as well as host epithelial cells and immune cells. Although the skin microbiota benefits the host by supporting the basic functions of the skin and preventing the colonization of pathogens, disruption of the microbial balance (dysbiosis) can cause skin diseases such as AD. Although AD is a dermatological disease, recent evidence has shown that changes in microbiota composition in the skin and intestine contribute to the pathogenesis of AD. Environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, diet, irritants, air pollution, epigenetics and microbial exposure. Knowing the microbial combination of intestin, as well as the genetic and epigenetic determinants associated with the development of autoantibodies, may help elucidate the pathophysiology of the disease. The skin of patients with AD is characterized by microbial dysbiosis as a result of reduced microbial diversity and overgrowth of the pathogens such as Staphylococcus aureus. Recent studies have revealed the importance of building a strong immune response against microorganisms during childhood and new mechanisms of microbial community dynamics in modulating the skin microbiome. Numerous microorganisms are reported to modulate host response through communication with keratinocytes, specific immune cells and adipocytes to improve skin health and barrier function. This growing insight into bioactive substances in the skin microbiota has led to novel biotherapeutic approaches targeting the skin surface for the treatment of AD. This review will provide an updated overview of the skin microbiota in AD and its complex interaction with immune response mechanisms, as well as explore possible underlying mechanisms in the pathogenesis of AD and provide insights into new therapeutic developments for the treatment of AD. It also focuses on restoring skin microbial homeostasis, aiming to reduce inflammation by repairing the skin barrier.

Programming Bordetella pertussis lipid A to promote adjuvanticity

BackgroundBordetella pertussis is the causative agent of whooping cough or pertussis. Although both acellular (aP) and whole-cell pertussis (wP) vaccines protect against disease, the wP vaccine, which is highly reactogenic, is better at preventing colonization and transmission. Reactogenicity is mainly attributed to the lipid A moiety of B. pertussis lipooligosaccharide (LOS). Within LOS, lipid A acts as a hydrophobic anchor, engaging with TLR4-MD2 on host immune cells to initiate both MyD88-dependent and TRIF-dependent pathways, thereby influencing adaptive immune responses. Lipid A variants, such as monophosphoryl lipid A (MPLA) can also act as adjuvants. Adjuvants may overcome the shortcomings of aP vaccines.ResultsThis work used lipid A modifying enzymes from other bacteria to produce an MPLA-like adjuvant strain in B. pertussis. We created B. pertussis strains with distinct lipid A modifications, which were validated using MALDI-TOF. We engineered a hexa-acylated monophosphorylated lipid A that markedly decreased human TLR4 activation and activated the TRIF pathway. The modified lipooligosaccharide (LOS) promoted IRF3 phosphorylation and type I interferon production, similar to MPLA responses. We generated three other variants with increased adjuvanticity properties and reduced endotoxicity. Pyrogenicity studies using the Monocyte Activation Test (MAT) revealed that these four lipid A variants significantly decreased the IL-6, a marker for fever, response in peripheral blood mononuclear cells (PBMCs).ConclusionThese findings pave the way for developing wP vaccines that are possibly less reactogenic and designing adaptable adjuvants for current vaccine formulations, advancing more effective immunization strategies against pertussis.

Emerging CRISPR-Based Therapeutics for HIV Eradication

Human Immunodeficiency Virus (HIV) continued to pose a major global health challenge, with current antiretroviral therapies unable to fully eradicate the virus due to latent reservoirs and potential drug resistance. Emerging CRISPR-based gene editing technologies had the potential to revolutionize HIV treatment by targeting and disrupting the viral genome or modifying host cells to confer resistance. This article explored the mechanisms of CRISPR in HIV therapeutics, including excision of integrated HIV proviruses and genetic editing of host immune cells. It reviewed progress in CRISPR-based research through in vitro studies, animal models, and early clinical trials, highlighting both promising advancements and ongoing challenges such as delivery efficiency, off-target effects, and viral escape. The methodology employed in writing this review paper involved a comprehensive literature review and synthesis of recent research findings to assess the current state and future directions of CRISPR-based HIV therapies. Despite significant progress, challenges remained, and future research will need to focus on improving delivery systems, combining CRISPR with other therapies, and optimizing gene editing in stem cells to achieve long-term HIV eradication. Keywords: CRISPR-Cas9, HIV Therapy, Gene Editing, Latent Reservoirs, CCR5 Receptor.

Immune cell kinetics after allogeneic red blood cell transfusion in patients undergoing cardiovascular surgery

Background and ObjectivesRecent reports have highlighted that allogeneic blood transfusions decrease immune responses and affect patient outcomes. However, the effects of allogeneic red blood cell transfusions on the composition of immune cells are unclear. We aimed to clarify the alterations in host immune cells in patients who received allogeneic red blood cell transfusions during the perioperative period of cardiovascular surgery. Materials and MethodsEight non-transfused, 22 intraoperative autotransfusions, and 36 allogeneic red blood cell-transfused patients undergoing surgery were grouped, and lymphocyte subsets were analyzed using flow cytometry. Blood samples collected before surgery, approximately 1-week, and 1-month after surgery were used for analysis. Surgical parameters, operation time, blood loss, and length of hospital stay were also assessed. ResultsThe group receiving transfusions showed statistical significance compared to non-transfused in the above-mentioned surgical parameters. When comparing the autologous and allogeneic transfusion groups, only the allogeneic red blood transfusion group had a longer hospital stay. In comparing preoperative and 1-week and 1-month postoperative samples, there were almost no differences in CD4, CD20, or NK counts between the autotransfusions and the allogenic red blood cell transfusion groups. In contrast, a significant decrease in lymphocyte count was observed in the allogenic red blood cell transfused group 1-week postoperatively compared to preoperatively. Moreover, the number of CD8 + cells was statistically lowest in the allogeneic transfusion group 1 week after the operation. ConclusionOur results suggest that allogeneic red blood cell transfusion could alter immune cell composition especially CD8 + cells, potentially impacting immune function.

Transcriptomic analysis reveals bovine herpesvirus 1 infection regulates innate immune response resulted in restricted viral replication in neuronal cells

BackgroundBovine herpesvirus 1 (BoHV-1) is a major pathogen that affects the global bovine population, primarily inducing respiratory and reproductive disorders. Its ability to establish latent infections in neuronal cells and to reactivate under certain conditions poses a continual threat to uninfected hosts. In this study, we aimed to analyze the replication characteristics of BoHV-1 in neuronal cells, as well as the effects of viral replication on host cell immunity and physiology. MethodsUsing the Neuro-2a neuronal-origin cell line as a model, we explored the dynamics of BoHV-1 replication and analyzed differential gene expression profiles post-BoHV-1 infection using high-throughput RNA sequencing. ResultsBoHV-1 demonstrated restricted replication in Neuro-2a cells. BoHV-1 induced apoptotic pathways and enhanced the transcription of interferon-stimulated genes and interferon regulatory factors while suppressing the complement cascade in Neuro-2a cells. ConclusionsDifferent from BoHV-1 infection in other non-highly differentiated somatic cells result in viral dominance, BoHV-1 regulated the innate immune response in neuronal cells formed a “virus-nerve cell” relative equilibrium state, which may account for the restricted replication of BoHV-1 in neuronal cells, leading to a latent infection. These findings provide a foundation for further research into the mechanism underlying BoHV-1-induced latent infection in nerve cells.

Borrelia burgdorferi Secretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts.

Borrelia burgdorferi , the bacteria that causes Lyme disease, induces a robust host immune response, including the production of type-I interferon (IFN-I). While this response helps combat the infection, it also contributes to complications such as Lyme arthritis. Our research aimed to identify the specific bacterial component that triggers the IFN-I response. We discovered that Borrelia burgdorferi releases a second messenger molecule, cyclic-di-adenosine monophosphate (c-di-AMP), which is recognized by host immune cells and subsequently triggers IFN-I production. This finding is significant as it advances our understanding of Lyme disease pathogenesis and offers a new strategy to tackle Lyme disease by targeting the production of c-di-AMP, in which we may be able to reduce the severity of the disease and mitigate long-term tissue damage. Borrelia burgdorferi c-di-AMP induces Type I IFN response.

Antibody-mediated control mechanisms of viral infections.

Antibodies generated after vaccination or natural pathogen exposure are essential mediators of protection against many infections. Most studies with viruses have focused on antibody neutralization, in which protection is conferred by the fragment antigen binding region (Fab) through targeting of different steps in the viral lifecycle including attachment, internalization, fusion, and egress. Beyond neutralization, the fragment crystallizable (Fc) region of antibodies can integrate innate and adaptive immune responses by engaging complement components and distinct Fc gamma receptors (FcγR) on different host immune cells. In this review, we discuss recent advances in our understanding of antibody neutralization and Fc effector functions, and the assays used to measure them. Additionally, we describe the contexts in which these mechanisms are associated with protection against viruses and highlight how Fc-FcγR interactions can improve the potency of antibody-based therapies.

Isolation of Staphylococcus pseudintermedius in Immunocompromised Patients from a Single Center in Spain: A Zoonotic Pathogen from Companion Animals.

Staphylococcus pseudintermedius, a commensal opportunistic bacterium predominantly residing in the skin of companion animals, particularly dogs, has the potential to induce skin and soft tissue infections in pets, and zoonotic infections, including catheter-related complications. This study documents four cases of S. pseudintermedius infection or colonization in patients who had close contact with dogs or cats. Identification of the bacterial species was performed using MALDI-TOF mass spectrometry, and antibiotic susceptibility was determined using microdilution assay. DNA was sequenced using Nanopore technology followed by in silico analysis. Three isolates were multidrug resistant, including resistance to methicillin, with one belonging to the prevalent European lineage ST551, and the other two were attributed to a novel multilocus sequence type, ST2672. The remaining isolate was attributed to the novel multilocus sequence type ST2673 and was methicillin susceptible. All four isolates exhibited an array of virulence factors that contributed to colonization, damage to host immune cells, and biofilm formation. All the ST551 isolates included in the comparative analysis displayed clonality within the European continent. The importance of describing zoonotic infections associated with S. pseudintermedius resides in the scarcity of available scientific literature, further accentuated by its heightened resistance profile and potential complications, particularly in the context of catheter-related infections.

Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.

High-throughput screening identifies ibuprofen as an sEV PD-L1 inhibitor for synergistic cancer immunotherapy

Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) limits therapeutic effectiveness by interacting with the PD-1 receptor on host immune cells. Targeting the secretion of sEV PD-L1 has emerged as a promising strategy to enhance immunotherapy. However, the lack of small-molecule inhibitors poses a challenge for clinical translation. In this study, we developed a target and phenotype dual-driven high-throughput screening (TAP-HTS) strategy that combined virtual screening with nanoflow-based experimental verification. We identified ibuprofen (IBP) as a novel inhibitor that effectively targeted sEV PD-L1 secretion. IBP disrupted the biogenesis and secretion of PD-L1+ sEVs in tumor cells by physically interacting with a critical regulator of sEV biogenesis, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS). Notably, the mechanism of action of IBP is distinct from its commonly known targets, cyclooxygenases (COX1 or COX2). Administration of IBP stimulated antitumor immunity and enhanced the efficacy of anti-PD-1 therapy in melanoma and oral squamous cell carcinoma (OSCC) mouse models. To address potential adverse effects, we further developed an IBP gel for topical application, which demonstrated remarkable therapeutic efficacy when combined with anti-PD-1 treatment. The discovery of this specific small inhibitor provides a promising avenue for establishing durable, systemic antitumor immunity.

Micron-scale topographies affect phagocytosis of bacterial cells on polydimethylsiloxane surfaces

Many medical devices implanted in patients to mitigate diseases and medical conditions have different types of topographic features. While appropriate textures can promote the integration of host cells and reduce scar tissue formation, some textured implants with inappropriate topographies have been associated with inflammation, bacterial colonization, or even malignant complications. To better understand how surface topography affects host immune response to colonizing bacteria, a protocol was developed to investigate phagocytosis of bacterial cells attached on polydimethylsiloxane (PDMS) surfaces with different square-shaped recessive patterns. The interaction between activated RAW 264.7 macrophages and Escherichia coli in recessive wells was visualized in 3D using multiple fluorescent markers. The results revealed that there is a threshold dimension of topography, below which phagocytosis of attached bacterial cells is significantly impeded. Specifically, under our experimental condition, up to 100-fold reduction in phagocytosis was observed in square-shaped patterns with 5 µm side length and 10 µm depth compared to the flat control and patterns with 10 µm or longer side length. The spacing between wells also showed significant effects; e.g., phagocytosis in the wells further decreased when spacing increased to 50 µm. These results are helpful for understanding how undesired topographies may contribute to bacterial colonization and thus infection and other associated complications. Statement of significanceSurface topography plays an important role in bacteria-material infections and thus the safety of implantable medical devices. Undesired topographic features can cause biofilm formation and related complications. However, how surface topography affects the capability of host immune cells to clear colonizing bacteria is not well understood. In this study, the interaction between macrophage RAW264.7 and colonizing E. coli cells on polydimethylsiloxane (PDMS) with recessive features is investigated. It was discovered that the size of recessive features and the spacing between these features have significant effects on phagocytosis of bacteria by macrophages. These new results are helpful for understanding the complex interaction among host cells, bacteria, and implanted biomaterials, which will help guide the rational design of safer medical devices.

Matrix design for optimal pancreatic β cells transplantation

New therapeutic approaches to treat type 1 diabetes mellitus relies on pancreatic islet transplantation. Here, developing immuno-isolation strategies is essential to eliminate the need for systemic immunosuppression after pancreatic islet grafts. A solution is the macro-encapsulation of grafts in semipermeable matrixes with a double function: separating islets from host immune cells and facilitating the diffusion of insulin, glucose, and other metabolites.This study aims to synthesize and characterize different types of gelatin-collagen matrixes to prepare a macro-encapsulation device for pancreatic islets that fulfill these functions. While natural polymers exhibit superior biocompatibility compared to synthetic ones, their mechanical properties are challenging to reproduce. To address this issue, we conducted a comparative analysis between photo-crosslinked gelatin matrixes and chemically crosslinked collagen matrixes. We show that the different crosslinkers and polymerization methods influence the survival and glucose-stimulated insulin production of pancreatic β cells (INS1) in vitro, as well as the in vitro and in vivo stability of the matrix and the immuno-isolation in vivo.Among the matrixes, the stiff multilayer GelMA matrixes (8.5 kPa), fabricated by digital light processing, were the best suited for pancreatic β cells macro-encapsulation regarding these parameters. Within the alveoli of this matrix, pancreatic β cells spontaneously formed aggregates.

Nanosensor-Enabled Detection and Identification of Intracellular Bacterial Infections in Macrophages.

Opportunistic bacterial pathogens can evade the immune response by residing and reproducing within host immune cells, including macrophages. These intracellular infections provide reservoirs for pathogens that enhance the progression of infections and inhibit therapeutic strategies. Current sensing strategies for intracellular infections generally use immunosensing of specific biomarkers on the cell surface or polymerase chain reaction (PCR) of the corresponding nucleic acids, making detection difficult, time-consuming, and challenging to generalize. Intracellular infections can induce changes in macrophage glycosylation, providing a potential strategy for signature-based detection of intracellular infections. We report here the detection of bacterial infection in macrophages using a boronic acid (BA)-based pH-responsive polymer sensor array engineered to distinguish mammalian cell phenotypes by their cell surface glycosylation signatures. The sensor was able to discriminate between different infecting bacteria in minutes, providing a promising tool for diagnostic and screening applications.

Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP kinase inhibition against BRAF-mutated melanoma

The implementation of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of patients with melanoma still remain refractory or acquire resistance to these new forms of treatment, illustrating a need for improvement. Here, we report that the clinically relevant combination of mitogen-activated protein (MAP) kinase pathway inhibitors dabrafenib and trametinib synergize with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed individual therapies. Our study suggests that agonist-induced activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of patients with melanoma receiving MAP kinase inhibitors.