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Human leukocyte antigen (HLA) class I peptide ligands (HLAIps) are key targets for developing vaccines and immunotherapies against infectious pathogens or cancer cells. Identifying HLAIps is challenging due to their high diversity, low abundance, and patient individuality. Here, we develop a highly sensitive method for identifying HLAIps using liquid chromatography-ion mobility-tandem mass spectrometry (LC-IMS-MS/MS). In addition, we train a timsTOF-specific peak intensity MS 2 PIP model for tryptic and non-tryptic peptides and implement it in MS 2 Rescore (v3) together with the CCS predictor from ionmob. The optimized method, Thunder-DDA-PASEF, semi-selectively fragments singly and multiply charged HLAIps based on their IMS and m/z. Moreover, the method employs the high sensitivity mode and extended IMS resolution with fewer MS/MS frames (300 ms TIMS ramp, 3 MS/MS frames), doubling the coverage of immunopeptidomics analyses, compared to the proteomics-tailored DDA-PASEF (100 ms TIMS ramp, 10 MS/MS frames). Additionally, rescoring boosts the HLAIps identification by 41.7% to 33%, resulting in 5738 HLAIps from as little as one million JY cell equivalents, and 14,516 HLAIps from 20 million. This enables in-depth profiling of HLAIps from diverse human cell lines and human plasma. Finally, profiling JY and Raji cells transfected to express the SARS-CoV-2 spike protein results in 16 spike HLAIps, thirteen of which have been reported to elicit immune responses in human patients., (© 2024. The Author(s).)

Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA 2 ). In our present work, we revealed the therapeutic effect of DIVA 2 in an MC38 tumor model and specifically focused on the mechanisms induced in the TME after immunization. DIVA 2 resulted in transient tumor control followed by an immune evasion phase within three weeks after the initial tumor inoculation. High-dimensional flow cytometry analysis and single-cell mRNA-sequencing of tumor-infiltrating leukocytes revealed cytotoxic CD8 + T cells as key players in the immune control phase. In the immune evasion phase, inflammatory CCR2 + PDL-1 + monocytes with immunosuppressive properties were recruited into the tumor leading to suppression of DIVA 2 -induced tumor-reactive T cells. Depletion of CCR2 + cells with specific antibodies resulted in prolonged survival revealing CCR2 + monocytes as important for tumor immune escape in the TME. In summary, the present work provides a platform for generating a strong antigen-specific primary and memory T cell immune response using the optimized transcutaneous immunization method DIVA 2 . This enables protection against tumors by therapeutic immune control of solid tumors and highlights the immunosuppressive influence of tumor infiltrating CCR2 + monocytes that need to be inactivated in addition for successful cancer immunotherapy., Competing Interests: A-KH, MS, MR are inventors of a patent application submitted by the UMC Mainz EP 18204287.9. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Bartneck, Hartmann, Stein, Arnold-Schild, Klein, Stassen, Marini, Pielenhofer, Meiser, Langguth, Mack, Muth, Probst, Schild and Radsak.)

Introduction: Transcutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic drug dithranol as novel TCI platform DIVA (dithranol/IMQ based vaccination). In extension of this work, we further optimized DIVA in terms of drug dose, application pattern and established a new IMQ formulation., Methods: C57BL/6 mice were treated on the ear skin with dithranol and IMQ-containing ointments together with ovalbumin-derived peptides. T cell responses were determined by flow cytometry and IFN-ɤ ELISpot assay, local skin inflammation was characterized by ear swelling., Results: Applying the adjuvants on separate skin sites, a reduced number of specific CD8 + T cells with effector function was detectable, indicating that the local concurrence of adjuvants and peptide antigens is required for optimal vaccination. Likewise, changing the order of dithranol and IMQ resulted in an increased skin inflammatory reaction, but lower frequencies of antigen-specific CD8 + T cells indicating that dithranol is essential for superior T cell priming upon DIVA. Dispersing nanocrystalline IMQ in a spreadable formulation (IMI-Sol+) facilitated storage and application rendering comparable immune responses. DIVA applied one or two weeks after the first immunization resulted in a massive increase in antigen-specific T cells and up to a ten-fold increased memory response. Finally, in a prophylactic tumor setting, double but no single DIVA treatment enabled complete control of tumor growth, resulting in full tumor protection., Discussion: Taken together, the described optimized transcutaneous vaccination method leads to the generation of a strong cellular immune response enabling the effective control of tumor growth and has the potential for clinical development as a novel non-invasive vaccination method for peptide-based cancer vaccines in humans., Competing Interests: A-KH and MR are inventors of a patent application submitted by the UMC Mainz EP 18204287.9. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hartmann, Bartneck, Pielenhofer, Meiser, Arnold-Schild, Klein, Stassen, Schild, Muth, Probst, Langguth, Grabbe and Radsak.)

The analysis of the secretome provides important information on proteins defining intercellular communication and the recruitment and behavior of cells in specific tissues. Especially in the context of tumors, secretome data can support decisions for diagnosis and therapy. The mass spectrometry-based analysis of cell-conditioned media is widely used for the unbiased characterization of cancer secretomes in vitro. Metabolic labeling using azide-containing amino acid analogs in combination with click chemistry facilitates this type of analysis in the presence of serum, preventing serum starvation-induced effects. The modified amino acid analogs, however, are less efficiently incorporated into newly synthesized proteins and may perturb protein folding. Combining transcriptome and proteome analysis, we elucidate in detail the effects of metabolic labeling with the methionine analog azidohomoalanine (AHA) on gene and protein expression. Our data reveal that 15-39% of the proteins detected in the secretome displayed changes in transcript and protein expression induced by AHA labeling. Gene Ontology (GO) analyses indicate that metabolic labeling using AHA leads to induction of cellular stress and apoptosis-related pathways and provide first insights on how this affects the composition of the secretome on a global scale. KEY MESSAGES: Azide-containing amino acid analogs affect gene expression profiles. Azide-containing amino acid analogs influence cellular proteome. Azidohomoalanine labeling induces cellular stress and apoptotic pathways. Secretome consists of proteins with dysregulated expression profiles., (© 2023. The Author(s).)

The generation of specific humoral and cellular immune responses plays a pivotal role in the development of effective vaccines against tumors. Especially the presence of antigen-specific, cytotoxic T cells influences the outcome of therapeutic cancer vaccinations. Different strategies, ranging from delivering antigen-encoding mRNAs to peptides or full antigens, are accessible but often suffer from insufficient immunogenicity and require immune-boosting adjuvants as well as carrier platforms to ensure stability and adequate retention. Here, we introduce a pH-responsive nanogel platform as a two-component antitumor vaccine that is safe for intravenous application and elicits robust immune responses in vitro and in vivo . The underlying chemical design allows for straightforward covalent attachment of a model antigen (ovalbumin) and an immune adjuvant (imidazoquinoline-type TLR7/8 agonist) onto the same nanocarrier system. In addition to eliciting antigen-specific T and B cell responses that outperform mixtures of individual components, our two-component nanovaccine leads in prophylactic and therapeutic studies to an antigen-specific growth reduction of different tumors expressing ovalbumin intracellularly or on their surface. Regarding the versatile opportunities for functionalization, our nanogels are promising for the development of highly customized and potent nanovaccines.

Tumors exhibit a variety of strategies to dampen antitumor immune responses. With an aim to identify factors that are secreted from tumor cells, we performed an unbiased mass spectrometry-based secretome analysis in lung cancer cells. Interleukin-6 (IL-6) has been identified as a prominent factor secreted by tumor cells and cancer-associated fibroblasts isolated from cancer patients. Incubation of dendritic cell (DC) cultures with tumor cell supernatants inhibited the production of IL-12p70 in DCs but not the surface expression of other activation markers which is reversed by treatment with IL-6 antibody. Defects in IL-12p70 production in the DCs inhibited the differentiation of Th1 but not Th2 and Th17 cells from naïve CD4 + T cells. We also demonstrate that the classical mitogen-activated protein kinase, ERK5/MAPK7, is required for IL-6 production in tumor cells. Inhibition of ERK5 activity or depletion of ERK5 prevented IL-6 production in tumor cells, which could be exploited for enhancing antitumor immune responses., (© 2021. The Author(s).)

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.

Background: We have previously developed a candidate therapeutic HPV DNA vaccine (pBI-11) encoding mycobacteria heat shock protein 70 linked to HPV16/18 E6/E7 proteins for the control of advanced HPV-associated oropharyngeal cancer (NCT05799144). While naked DNA vaccines are readily produced, stable, and well tolerated, their potency is limited by the delivery efficiency. Here we compared three different IM delivery strategies, including intramuscular (IM) injection, either with a needle alone or with electroporation at the injection site, and a needle-free injection system (NFIS), for their ability to elicit gene expression and to improve the potency of pBI-11 DNA vaccine. Results: We found that electroporation after IM injection significantly increases gene expression from a luciferase-encoding DNA construct compared to IM injection alone or NFIS. We also showed that single administration of pBI-11 DNA via electroporation-mediated delivery generates the greatest increase in HPV antigen-specific CD8 + T cell-mediated immune responses, resulting in the most potent antitumor effect compared to the other two methods. We further compared the response to three repeat immunizations via each of these different methods. We found that electroporation-mediated delivery of pBI-11 DNA generates the greatest HPV antigen-specific CD8 + T cell immune responses and therapeutic antitumor effects compared to the other two methods. Monitoring of mouse behaviors and body weight, and necropsy indicated that electroporation-mediated delivery of clinical grade pBI-11 DNA vaccine was well-tolerated and presented no evident local or systemic toxicity. Conclusions: These findings provide rationale for clinical testing of pBI-11 DNA vaccine delivered by electroporation for the control of HPV16/18-associated infections and/or cancers. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease.

The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia, and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increase susceptibility to oxidative stress, lipotoxicity, and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions and of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis, and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells. [ABSTRACT FROM AUTHOR]

Introduction: The introduction of trapped ion mobility spectrometry (TIMS) in combination with fast high-resolution time-of-flight (TOF) mass spectrometry to the proteomics field led to a jump in protein identifications and quantifications, as well as a lowering of the limit of detection for proteins from biological samples. Parallel Accumulation-Serial Fragmentation (PASEF) is a driving force for this development and has been adapted to discovery as well as targeted proteomics. Areas covered: Over the last decade, the PASEF concept has been optimized and led to the implementation of eleven new measurement techniques. In this review, we describe all currently described PASEF measurement techniques and their application to clinical proteomics. Literature was searched using PubMed and Google Scholar search engines. Expert Opinion: The use of a dual TIMS tunnel has revolutionized the depth and the speed of proteomics measurements. Currently, we witness how this technique is pushing clinical proteomics forward. [ABSTRACT FROM AUTHOR]

Immunopeptidomics is the area of knowledge focused on the study of peptides assembled in the major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, which could activate the immune response via specific and selective T cell recognition. Advances in high-sensitivity mass spectrometry have enabled the detailed identification and quantification of the immunopeptidome, significantly impacting fields like oncology, infections, and autoimmune diseases. Current immunopeptidomics approaches primarily focus on workflows to identify immunopeptides from HLA molecules, requiring the isolation of the HLA from relevant cells or tissues. Common critical steps in these workflows, such as cell lysis, HLA immunoenrichment, and peptide isolation, significantly influence outcomes. A systematic evaluation of these steps led to the creation of an 'Immunopeptidome Score' to enhance the reproducibility and robustness of these workflows. This score, derived from LC-MS/MS datasets (ProteomeXchange identifier PXD038165), in combination with available information from public databases, aids in optimizing the immunopeptidome characterization process. The 'Immunopeptidome Score' has been applied in a systematic analysis of protein extraction, HLA immunoprecipitation, and peptide recovery yields across several tumor cell lines enabling the selection of peptides with optimal features and, therefore, the identification of potential biomarker and therapeutic targets. [ABSTRACT FROM AUTHOR]

Photothermal therapy is an alternative cancer therapy that uses a photothermal agent with light irradiation to induce fatal hyperthermia in cancer cells. In a previous study, we found that ex vivo photothermal (PT) treatment induced expression of heat shock proteins (HSPs), such as HSP70, HSP27, and HSP90, in cancer cells; moreover, immunization with lysates from PT-treated tumor cells resulted in significant tumor growth inhibition in tumor-bearing mice. In this study, we hypothesized that sublethal PT treatment of antigen-presenting cells regulates their immunogenicity. We observed the upregulation of expression of intracellular HSP70 and surface activation markers, such as CD40, CD80, CD86, and MHC class II, in sublethal PT-treated cells. The protumoral activity of myeloid-derived suppressor cells (MDSCs) was reduced by sublethal hyperthermia. Furthermore, poorly immunogenic MDSCs were converted into immunogenic antigen-presenting cells by PT treatment. The differences in immunogenicity between MDSCs untreated or treated with the PT technique were evaluated using the Student's t-test or Mann–Whitney rank sum test. Collectively, direct hyperthermic treatment resulted in phenotypic changes and the functional regulation of immune cells. [ABSTRACT FROM AUTHOR]

Immunotherapy has made significant strides in cancer treatment with strategies like checkpoint blockade antibodies and adoptive T cell transfer. Chimeric antigen receptor T cells (CAR-T) have emerged as a promising approach to combine these strategies and overcome their limitations. This review explores CAR-T cells as a living drug for cancer treatment. CAR-T cells are genetically engineered immune cells designed to target and eliminate tumor cells by recognizing specific antigens. The study involves a comprehensive literature review on CAR-T cell technology, covering structure optimization, generations, manufacturing processes, and gene therapy strategies. It examines CAR-T therapy in haematologic cancers and solid tumors, highlighting challenges and proposing a suicide gene-based mechanism to enhance safety. The results show significant advancements in CAR-T technology, particularly in structure optimization and generation. The manufacturing process has improved for broader clinical application. However, a series of inherent challenges and side effects still need to be addressed. In conclusion, CAR-T cells hold great promise for cancer treatment, but ongoing research is crucial to improve efficacy and safety for oncology patients. The proposed suicide gene-based mechanism offers a potential solution to mitigate side effects including cytokine release syndrome (the most common toxic side effect of CAR-T therapy) and the associated neurotoxicity. [ABSTRACT FROM AUTHOR]

With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as potential therapeutic strategies. A systematic review and analysis must be carried out to investigate the effect of mannose modification on the immune response to nanoparticles in regulating the tumor microenvironment, as well as to explore its potential clinical application in tumor therapy. Despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and the overexpression of immunosuppressive factors limit its clinical application. Therefore, our review explored how to intervene in the immunosuppressive mechanism in the tumor microenvironment through the use of mannan-decorated lipid calcium phosphate nanoparticle vaccines to improve the efficacy of immunotherapy in patients with tumors and to provide new ideas and strategies for the field of tumor therapy. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSPs) have been described as potent tumor vaccines in animal models and are currently studied in clinical trials. The underlying immune response relies on immunogenic peptides that the HSPs have acquired intracellularly by interfering with the classical antigen processing pathways. There have been numerous reports shedding light on how HSPs are able to gain this function and a number of important requirements for HSP-mediated specific immunity have been described: first, the ability of HSPs to bind immunogenic peptides. Second, the acquisition of HSPs by specialized antigen presenting cells with efficient antigen processing pathways capable of inducing cellular immune responses. Third, the existence of specific receptors on the surfaces of antigen presenting cells, allowing efficient and rapid uptake of HSP-peptide complexes from the extracellular fluid. And fourth, the ability of heat shock proteins to activate antigen presenting cells, enabling the latter to prime cytotoxic T cell responses against the peptides associated to HSPs.

Heat shock proteins like gp96 (grp94) are able to induce specific cytotoxic T-cell (CTL) responses against cells from which they originate and are currently studied in clinical trials for use in immunotherapy of tumors. We have recently demonstrated that gp96 binds to at least one yet unidentified receptor restricted to antigen-presenting cells (APCs) like dendritic cells (DCs) but not to T cells. Moreover we have shown, that for CTL activation by gp96-chaperoned peptides receptor-mediated uptake of gp96 by APCs is required. Lately, we have discovered a second function of gp96 when interacting with professional APCs. Gp96 is able to mediate maturation of DCs as determined by upregulation of MHC class II, CD86 and CD83 molecules, secretion of pro-inflammatory cytokines IL-12 and TNF-alpha and enhanced T-cell simulatory capacity. Furthermore, the gp96 receptor(s) are down-regulated on mature DCs, suggesting that the gp96 receptor(s) behave similar to other endocytic receptors like CD36, mannose receptor etc. Our findings now provide additional evidence for the remarkable immunogenicity of gp96: first, the existence of specific gp96 receptors on APCs and second, the capacity to activate dendritic cells which is strictly required to enable these highly sophisticated APCs to prime CTL responses.

Heat shock proteins such as gp96 (grp94) isolated from tumor or infected cells are able to induce specific cytotoxic T-cell responses and protective immunity. To facilitate rapid and efficient isolation, we generated gp96-specific recombinant single-chain Fv (scFv) antibodies from a semisynthetic phage display library. When immobilized on Sepharose beads, these antibodies allow a high-yield, one-step purification of native gp96 molecules from both mouse and human tumor cell lysates. gp96 molecules eluted from these affinity columns under mild conditions are still capable of generating antigen-specific CTL responses in mice. Thus, scFv-purified gp96 is still associated with peptides; however, in contrast to conventionally purified gp96, scFv-isolated gp96 is free of contaminating material such as mitogenic concanavalin A and proteolytic cathepsins. With the help of these high-yield antibody columns, it is now possible to rapidly isolate immunogenic gp96-peptide complexes from small amounts of tumor material to a purity that allows their use in cancer immunotherapy protocols.

Peptides associated with the heat shock protein gp96 induce a specific T cell response against cells from which gp96 is isolated. Recently, we have shown that gp96 binds to a yet unknown receptor present on dendritic cells (DC) and that receptor-mediated uptake is required for cross-presentation of gp96-associated peptides by DC. We now describe that gp96 mediates maturation of DC as determined by up-regulation of MHC class II and CD86 molecules, secretion of the cytokines IL-12 and TNF-alpha and enhanced T cell stimulatory capacity. Heat-denatured gp96 is not able to induce DC maturation and cytokine secretion. Furthermore, we show that mature DC are no longer able to bind gp96 molecules. Hence, the gp96 receptor is down-regulated on mature DC, suggesting that this receptor behaves similar to other receptors involved in antigen uptake like the scavenger receptor CD36, the mannose receptor or the integrins alpha(v)beta(3) and alpha(v)beta(5). Together, our findings provide an additional explanation for the remarkable immunogenicity of gp96 as a cross-priming antigen carrier and direct activator of DC.

Heat shock proteins (HSPs) like glycoprotein (gp)96 (glucose-regulated protein 94 [grp94]) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. Here, we demonstrate that for CTL activation by gp96-chaperoned peptides, specific receptor-mediated uptake of gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind gp96. The binding is saturable and can be inhibited using unlabeled gp96 molecules. Receptor binding by APCs leads to a rapid internalization of gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1B-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of gp96 molecules leads to MHC class I-restricted re-presentation of gp96-associated peptides and CTL activation; non-receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which gp96 is participating in the cross-presentation of antigens from cellular origin.

Chaperone molecules, including members of the heat shock protein family, are able to stimulate alphabeta and gammadelta T cells as well as natural killer cells. For alphabeta T cells, specificity is induced by chaperone-assisted peptides; this has lead to detailed investigations of peptides that bind to these chaperones and their possible role in antigen presentation.

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is contextdependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity. [ABSTRACT FROM AUTHOR]

Bones are vital for anchoring muscles, tendons, and ligaments, serving as a fundamental element of the human skeletal structure. However, our understanding of bone development mechanisms and the maintenance of bone homeostasis is still limited. Extracellular signal-related kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in the pathogenesis and progression of various diseases, especially neoplasms. Recent studies have highlighted ERK5's significant role in both bone development and bone-associated pathologies. This review offers a detailed examination of the latest research on ERK5 in different tissues and diseases, with a particular focus on its implications for bone health. It also examines therapeutic strategies and future research avenues targeting ERK5. [ABSTRACT FROM AUTHOR]

The concept of nanomedicine has evolved significantly in recent decades, leveraging the unique phenomenon known as the enhanced permeability and retention (EPR) effect. This has facilitated major advancements in targeted drug delivery, imaging, and individualized therapy through the integration of nanotechnology principles into medicine. Numerous nanomedicines have been developed and applied for disease treatment, with a particular focus on cancer therapy. Recently, nanomedicine has been utilized in various advanced fields, including diagnosis, vaccines, immunotherapy, gene delivery, and tissue engineering. Multifunctional nanomedicines facilitate concurrent medication delivery, therapeutic monitoring, and imaging, allowing for immediate responses and personalized treatment plans. This review concerns the major advancement of nanomaterials and their potential applications in the biological and medical fields. Along with this, we also mention the various clinical translations of nanomedicine and the major challenges that nanomedicine is currently facing to overcome the clinical translation barrier. [ABSTRACT FROM AUTHOR]

Background: Exosomes, nano-sized extracellular vesicles, have emerged as a promising tool for the diagnosis and treatment of various intractable diseases, including chronic wounds and cancers. As our understanding of exosomes continues to grow, their potential as a powerful therapeutic modality in medicine is also expanding. This systematic review aims to examine the progress of exosome-based clinical trials and provide a comprehensive overview of the therapeutic perspectives of exosomes., Methods: This systematic review strictly follows PRISMA guidelines and has been registered in PROSPERO, the International Prospective Register of Systematic Reviews. It encompasses articles from January 2000 to January 2023, sourced from bibliographic databases, with targeted search terms targeting exosome applications in clinical trials. During the screening process, strict inclusion and exclusion criteria were applied, including a focus on clinical trials utilizing different cell-derived exosomes for therapeutic purposes., Results: Among the 522 publications initially identified, only 10 studies met the stringent eligibility criteria after meticulous screening. The selection process involved systematically excluding duplicates and irrelevant articles to provide a transparent overview., Conclusion: According to our systematic review, exosomes have promising applications in a variety of medical fields, including cell-free therapies and drug delivery systems for treating a variety of diseases, especially cancers and chronic wounds. To ensure safety, potency, and broader clinical applications, further optimization of exosome extraction, loading, targeting, and administration is necessary. While cell-based therapeutics are increasingly utilizing exosomes, this field is still in its infancy, and ongoing clinical trials will provide valuable insights into the clinical utility of exosomes., Competing Interests: Declarations Ethics Approval This systematic review was conducted with the permission of the Ethics Committee for Urmia University of Medical Sciences (IR.UMSU.REC.1401.020). Consent for Publication Not applicable. Declaration of Generative AI in Scientific Writing During the preparation of this work the author(s) did not use generative AI tools. Competing Interests No competing interests are declared by the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

With significant advances in analytical technologies, research in the field of cancer immunotherapy, such as adoptive T cell therapy, cancer vaccine, and immune checkpoint blockade (ICB), is currently gaining tremendous momentum. Since the efficacy of cancer immunotherapy is recognized only by a minority of patients, more potent tumor‐specific antigens (TSAs, also known as neoantigens) and predictive markers for treatment response are of great interest. In cancer immunity, immunopeptides, presented by human leukocyte antigen (HLA) class I, play a role as initiating mediators of immunogenicity. The latest advancement in the interdisciplinary multiomics approach has rapidly enlightened us about the identity of the "dark matter" of cancer and the associated immunopeptides. In this field, mass spectrometry (MS) is a viable option to select because of the naturally processed and actually presented TSA candidates in order to grasp the whole picture of the immunopeptidome. In the past few years the search space has been enlarged by the multiomics approach, the sensitivity of mass spectrometers has been improved, and deep/machine‐learning‐supported peptide search algorithms have taken immunopeptidomics to the next level. In this review, along with the introduction of key technical advancements in immunopeptidomics, the potential and further directions of immunopeptidomics will be reviewed from the perspective of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

It has been 50 years since Peter Charles Doherty and Rolf M Zinkernagel proposed the principle of "simultaneous dual recognition", according to which adaptive immune cells recognized "self" and "non-self" simultaneously to establish immunological efficacy. These two scientists shared the 1996 Nobel Prize in Physiology or Medicine for this discovery. Their basic immunological principle became the foundation for the development of numerous vaccine approaches against infectious diseases and tumors, including promising strategies grounded on the use of recombinant gp96-Ig developed by our lab over the last two decades. In this review, we will highlight three major principles of the gp96-Ig vaccine strategy: (1) presentation of pathogenic antigens to T cells (specificity); (2) activation of innate immune responses (adjuvanticity); (3) priming of T cells to home to the epithelial compartments (mucosal immunity). In summary, we provide a paradigm for a vaccine approach that can be rapidly engineered and customized for any future pathogens that require induction of effective tissue-resident memory responses in epithelial tissues. [ABSTRACT FROM AUTHOR]

The bioprospecting of sea anemone tissues and secretions has revealed that they are natural libraries of polypeptides with diverse biological activities that can be utilized to develop of biotechnological tools with potential medical and industrial applications. This study conducted a proteomic analysis of crude venom extracts from Anthopleura dowii Verrill, 1869, and Lebrunia neglecta Duchassaing & Michelotti, 1860. The obtained data allowed us to identify 201 polypeptides, of which 39% were present in both extracts. Among the obtained sequences, hydrolase-type enzymes, oxidoreductases, transferases, heat shock proteins, adhesion proteins, and protease inhibitors, among others, were identified. Interaction analysis and functional annotation indicated that these proteins are primarily involved in endoplasmic reticulum metabolic processes such as carbon metabolism and protein processing. In addition, several proteins related to oxidative stress were identified, including superoxide dismutase, peroxiredoxins, thioredoxin, and glutathione oxidase. Our results provide novel information on the polypeptide composition of the crude venom extract from sea anemones, which can be utilized to develop molecules for therapeutic tools and industrial applications. [ABSTRACT FROM AUTHOR]

Co-delivery of antigens and adjuvants to the same antigen-presenting cells (APCs) can significantly improve the efficacy and safety profiles of vaccines. Here, we report amine-grafted silica nanoparticles (A-SNP) as a tunable vaccine co-delivery platform for TLR7/8 agonists along with the recombinant influenza antigen hemagglutinin H7 (H7) to APCs. A-SNP of two different sizes (50 and 200 nm) were prepared and coated with INI-4001 at different coating densities, followed by co-adsorption of H7. Both INI-4001 and H7 showed >90% adsorption to the tested A-SNP formulations. TNF-α and IFN-α cytokine release by human peripheral blood mononuclear cells as well as TNF-α, IL-6, and IL-12 release by mouse bone marrow-derived dendritic cells revealed that the potency of the INI-4001-adsorbed A-SNP (INI-4001/A-SNP) formulations was improved relative to aqueous formulation control. This improved potency was dependent on particle size and ligand coating density. In addition, slow-release profiles of INI-4001 were measured from INI-4001/A-SNP formulations in plasma with 30–50% INI-4001 released after 7 days. In vivo murine immunization studies demonstrated significantly improved H7-specific humoral and Th1/Th17-polarized T cell immune responses with no observed adverse reactions. Low-density 50 nm INI-4001/A-SNP elicited significantly higher IFN-γ and IL-17 induction over that of the H7 antigen-only group and INI-4001 aqueous formulation controls. In summary, this work introduces an effective and biocompatible SNP-based co-delivery platform that enhances the immunogenicity of TLR7/8 agonist-adjuvanted subunit influenza vaccines. [ABSTRACT FROM AUTHOR]

Background: The edible fungus Auricularia delicate (ADe) is commonly employed in traditional medicine for intestinal disorders; however, its inhibitory effect on colitis-associated colorectal cancer (CAC) and the underlying mechanisms remain unexplored. (2) Methods: The inhibitory effect of ADe on CAC was investigated using a mouse model induced by azoxymethane/dextran sulfate sodium. Results: ADe effectively suppressed the growth and number of intestinal tumors in mice. Intestinal microbiota analyses revealed that ADe treatment increased Akkermansia and Parabacteroides while it decreased Clostridium, Turicibacter, Oscillospira, and Desulfovibrio. ADe regulated the levels of 2′-deoxyridine, creatinine, 1-palmitoyl lysophosphatidylcholine, and choline in serum. Furthermore, the levels of these metabolites were associated with the abundance of Oscillospira and Paraacteroides. ADe up-regulated the free fatty acid receptor 2 and β-Arrestin 2, inhibited the nuclear factor kappa B (NF-κB) pathway, and significantly attenuated the levels of inflammatory cytokines, thereby mitigating the inflammatory in CAC mice. Conclusions: The protective effect of ADe in CAC mice is associated with the regulation of intestinal microbiota, which leads to the inhibition of NF-kB pathway and regulation of inflammation. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is one of the leading causes of mortality worldwide, primarily driven by atherosclerosis, a chronic inflammatory condition contributing significantly to fatalities. Various biological determinants affecting cardiovascular health across different age and sex groups have been identified. In this context, recent attention has focused on the potential therapeutic and preventive role of increasing circulating levels of heat shock protein 27 (plasma HSP27) in combating atherosclerosis. Plasma HSP27 is recognized for its protective function in inflammatory atherogenesis, offering promising avenues for intervention and management strategies against this prevalent cardiovascular ailment. Exercise has emerged as a pivotal strategy in preventing and managing cardiovascular disease, with literature indicating an increase in plasma HSP27 levels post-exercise. However, there is limited understanding of the impact of exercise on the release of HSP27 into circulation. Clarifying these aspects is crucial for understanding the role of exercise in modulating plasma HSP27 levels and its potential implications for cardiovascular health across diverse populations. Therefore, this review aims to establish a more comprehensive understanding of the relationship between plasma HSP27 and exercise., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA² ). In our present work, we revealed the therapeutic effect of DIVA² in an MC38 tumor model and specifically focused on the mechanisms induced in the TME after immunization. DIVA2 resulted in transient tumor control followed by an immune evasion phase within three weeks after the initial tumor inoculation. High-dimensional flow cytometry analysis and single-cell mRNA-sequencing of tumor-infiltrating leukocytes revealed cytotoxic CD8+ T cells as key players in the immune control phase. In the immune evasion phase, inflammatory CCR2+ PDL-1+ monocytes with immunosuppressive properties were recruited into the tumor leading to suppression of DIVA² -induced tumor-reactive T cells. Depletion of CCR2+ cells with specific antibodies resulted in prolonged survival revealing CCR2+ monocytes as important for tumor immune escape in the TME. In summary, the present work provides a platform for generating a strong antigen-specific primary and memory T cell immune response using the optimized transcutaneous immunization method DIVA² . This enables protection against tumors by therapeutic immune control of solid tumors and highlights the immunosuppressive influence of tumor infiltrating CCR2+ monocytes that need to be inactivated in addition for successful cancer immunotherapy [ABSTRACT FROM AUTHOR]

For successful therapeutic interventions in cancer immunotherapy, strong antigen-specific immune responses are required. To this end, immunostimulating cues must be combined with antigens to simultaneously arrive at antigen-presenting cells and initiate cellular immune responses. Recently, imidazoquinolines have shown their vast potential as small molecular Toll-like receptor 7/8 (TLR7/8) agonists for immunostimulation when delivered by nanocarriers. At the same time, peptide antigens are promising antigen candidates but require combination with immune-stimulating adjuvants to boost their immunogenicity and exploit their full potential. Consequently, we herein present biodegradable polycarbonate nanogels as versatile delivery system for adjuvants within the particles' core as well as for peptide antigens by surface decoration. For that purpose, orthogonally addressable multifunctional polycarbonate block copolymers were synthesized, enabling adjuvant conjugation through reactive ester chemistry and peptide decoration by strain-promoted alkyne-azide cycloaddition (SPAAC). In preparation for SPAAC, CD4+-specific peptide sequences of the model protein antigen ovalbumin were equipped with DBCO-moieties by site-selective modification at their N-terminal cysteine. With their azide groups exposed on their surface, the adjuvant-loaded nanogels were then efficiently decorated with DBCO-functional CD4+-peptides by SPAAC. In vitro evaluation of the adjuvant-loaded peptide-decorated gels then confirmed their strong immunostimulating properties as well as their high biocompatibility. Despite their covalent conjugation, the CD4+-peptide-decorated nanogels led to maturation of primary antigen-presenting cells and the downstream priming of CD4+-T cells. Subsequently, the peptide-decorated nanogels loaded with TLR7/8 agonist were successfully processed by antigen-presenting cells, enabling potent immune responses for future application in antigen-specific cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Asthma is a chronic airway inflammatory disease whose global incidence increases annually. The role of innate lymphoid cells (ILCs) is a crucial aspect of asthma research with respect to different endotypes of asthma. Based on its pathological and inflammatory features, asthma is divided into type 2 high and type 2 low endotypes. Type‐2 high asthma is distinguished by the activation of type 2 immune cells, including T helper 2 (Th2) cells and ILC2s; the production of cytokines interleukin (IL)‐4, IL‐5 and IL‐13; eosinophilic aggregation; and bronchial hyper‐responsiveness. Type‐2 low asthma represents a variety of endotypes other than type 2 high endotype such as the IL‐1β/ILC3/neutrophil endotype and a paucigranulocytic asthma, which may be insensitive to corticosteroid treatment and/or associated with obesity. The complexity of asthma is due to the involvement of multiple cell types, including tissue‐resident ILCs and other innate immune cells including bronchial epithelial cells, dendritic cells, macrophages and eosinophils, which provide immediate defence against viruses, pathogens and allergens. On this basis, innate immune cells and adaptive immune cells combine to induce the pathological condition of asthma. In addition, the plasticity of ILCs increases the heterogeneity of asthma. This review focuses on the phenotypes of tissue‐resident ILCs and their roles in the different endotypes of asthma, as well as the mechanisms of tissue‐resident ILCs and other immune cells. Based on the phenotypes, roles and mechanisms of immune cells, the therapeutic strategies for asthma are reviewed. [ABSTRACT FROM AUTHOR]

Tumor vaccines aim to activate dormant or unresponsive tumor-specific T lymphocytes by using tumor-specific or tumor-associated antigens, thus enhancing the body's natural defense against cancer. However, the effectiveness of tumor vaccines is limited by the presence of tumor heterogeneity, low immunogenicity, and immune evasion mechanisms. Fortunately, multifunctional nanoparticles offer a unique chance to address these issues. With the advantages of their small size, high stability, efficient drug delivery, and controlled surface chemistry, nanomaterials can precisely target tumor sites, improve the delivery of tumor antigens and immune adjuvants, reshape the immunosuppressive tumor microenvironment, and enhance the body's anti-tumor immune response, resulting in improved efficacy and reduced side effects. Nanovaccine, a type of vaccine that uses nanotechnology to deliver antigens and adjuvants to immune cells, has emerged as a promising strategy for cancer immunotherapy due to its ability to stimulate immune responses and induce tumor-specific immunity. In this review, we discussed the compositions and types of nanovaccine, and the mechanisms behind their anti-tumor effects based on the latest research. We hope that this will provide a more scientific basis for designing tumor vaccines and enhancing the effectiveness of tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Vaccine is one of the most promising strategies for cancer immunotherapy; however, there are no therapeutic cancer vaccine achieving significant clinical efficacy till now. The main limiting factors include the immune suppression and escape mechanisms developed by tumor and not enough capacity of vaccines to induce a vigorous anti-tumor immunity. This study aimed to develop a strategy of membrane-based biomimetic nanovaccine and investigate the immunological outcomes of utilizing the unique immunostimulatory mechanisms derived of immunogenic cell death (ICD) and of fulfilling a simultaneous nanoscale delivery of a highlighted tumor antigen and broad membrane-associated tumor antigens in the vaccine design. TC-1 tumor cells were treated in vitro with a mixture of mitoxantrone and curcumin for ICD induction, and then chitosan (CS)-coated polylactic co-glycolic acid (PLGA) nanoparticles loaded with HPV16 E744-62 peptides were decorated with the prepared ICD tumor cell membrane (IM); further, the IM-decorated nanoparticles along with adenosine triphosphate (ATP) were embedded with sodium alginate (ALG) hydrogel, And then, the immunological features and therapeutic potency were evaluated in vitro and in vivo. The nanovaccine significantly stimulated the migration, antigen uptake, and maturation of DCs in vitro, improved antigen lysosome escape, and promoted the retention at injection site and accumulation in LNs of the tumor antigen in vivo. In a subcutaneously grafted TC-1 tumor model, the therapeutic immunization of nanovaccine elicited a dramatical antitumor immunity. This study provides a strategy for the development of tumor vaccines. [ABSTRACT FROM AUTHOR]

Motivation Including ion mobility separation (IMS) into mass spectrometry proteomics experiments is useful to improve coverage and throughput. Many IMS devices enable linking experimentally derived mobility of an ion to its collisional cross-section (CCS), a highly reproducible physicochemical property dependent on the ion's mass, charge and conformation in the gas phase. Thus, known peptide ion mobilities can be used to tailor acquisition methods or to refine database search results. The large space of potential peptide sequences, driven also by posttranslational modifications of amino acids, motivates an in silico predictor for peptide CCS. Recent studies explored the general performance of varying machine-learning techniques, however, the workflow engineering part was of secondary importance. For the sake of applicability, such a tool should be generic, data driven, and offer the possibility to be easily adapted to individual workflows for experimental design and data processing. Results We created ionmob , a Python-based framework for data preparation, training, and prediction of collisional cross-section values of peptides. It is easily customizable and includes a set of pretrained, ready-to-use models and preprocessing routines for training and inference. Using a set of ≈21 000 unique phosphorylated peptides and ≈17 000 MHC ligand sequences and charge state pairs, we expand upon the space of peptides that can be integrated into CCS prediction. Lastly, we investigate the applicability of in silico predicted CCS to increase confidence in identified peptides by applying methods of re-scoring and demonstrate that predicted CCS values complement existing predictors for that task. Availability and implementation The Python package is available at github: https://github.com/theGreatHerrLebert/ionmob. [ABSTRACT FROM AUTHOR]

In this study, the impact of different delivery systems on the cytokine-inducing, antiproliferative, and antitumor activities of short immunostimulatory double-stranded RNA (isRNA) was investigated. The delivery systems, consisting of the polycationic amphiphile 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20 tetraazahexacosan tetrahydrochloride (2X3), and the lipid-helper dioleoylphosphatidylethanolamine (DOPE), were equipped with polyethylene glycol lipoconjugates differing in molecular weight and structure. The main findings of this work are as follows: (i) significant activation of MCP-1 and INF-α, β, and γ production in CBA mice occurs under the action of isRNA complexes with liposomes containing lipoconjugates with long PEG chains, while activation of MCP-1 and INF-γ, but not INF-α or β, was observed under the action of isRNA lipoplexes containing lipoconjugates with short PEG chains; (ii) a pronounced antiproliferative effect on B16 melanoma cells in vitro, as well as an antitumor and hepatoprotective effect in vivo, was induced by isRNA pre-complexes with non-pegylated liposomes, while complexes containing lipoconjugates with long-chain liposomes were inactive; (iii) the antitumor activity of isRNA correlated with the efficiency of its accumulation in the cells and did not explicitly depend on the activation of cytokine and interferon production. Thus, the structure of the delivery system plays a vital role in determining the response to isRNA and allows for the choice of a delivery system depending on the desired effect. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of many cancer types, including head and neck cancers (HNC). When checkpoint and partner proteins bind, these send an "off" signal to T cells, which prevents the immune system from destroying tumor cells. However, in HNC, and indeed many other cancers, more people do not respond and/or suffer from toxic effects than those who do respond. Hence, newer, more effective approaches are needed. The challenge to durable therapy lies in a deeper understanding of the complex interactions between immune cells, tumor cells and the tumor microenvironment. This will help develop therapies that promote lasting tumorlysis by overcoming T-cell exhaustion. Here we explore the strengths and limitations of current ICI therapy in head and neck squamous cell carcinoma (HNSCC). We also review emerging small-molecule immunotherapies and the growing promise of neutrophil extracellular traps in controlling tumor progression and metastasis. [ABSTRACT FROM AUTHOR]

The haemostatic system is pivotal to maintaining vascular integrity. Multiple components involved in blood coagulation have central functions in inflammation and immunity. A derailed haemostasis is common in prevalent pathologies such as sepsis, cardiovascular disorders, and lately, COVID-19. Physiological mechanisms limit the deleterious consequences of a hyperactivated haemostatic system through adaptive changes in gene expression. While this is mainly regulated at the level of transcription, co- and posttranscriptional mechanisms are increasingly perceived as central hubs governing multiple facets of the haemostatic system. This layer of regulation modulates the biogenesis of haemostatic components, for example in situations of increased turnover and demand. However, they can also be 'hijacked' in disease processes, thereby perpetuating and even causally entertaining associated pathologies. This review summarizes examples and emerging concepts that illustrate the importance of posttranscriptional mechanisms in haemostatic control and crosstalk with the immune system. It also discusses how such regulatory principles can be used to usher in new therapeutic concepts to combat global medical threats such as sepsis or cardiovascular disorders. [ABSTRACT FROM AUTHOR]

Purpose: Dysregulated metabolism is now recognized as a fundamental hallmark of carcinogenesis inducing aggressive features and additional hallmarks. In this review, well-established metabolic changes displayed by tumors are highlighted in a comprehensive manner and corresponding therapeutical targets are discussed to set up a framework for integrating basic research findings with clinical translation in oncology setting. Methods: Recent manuscripts of high research impact and relevant to the field from PubMed (2000–2021) have been reviewed for this article. Results: Metabolic pathway disruption during tumor evolution is a dynamic process potentiating cell survival, dormancy, proliferation and invasion even under dismal conditions. Apart from cancer cells, though, tumor microenvironment has an acting role as extracellular metabolites, pH alterations and stromal cells reciprocally interact with malignant cells, ultimately dictating tumor-promoting responses, disabling anti-tumor immunity and promoting resistance to treatments. Conclusion: In the field of cancer metabolism, there are several emerging prognostic and therapeutic targets either in the form of gene expression, enzyme activity or metabolites which could be exploited for clinical purposes; both standard-of-care and novel treatments may be evaluated in the context of metabolism rewiring and indeed, synergistic effects between metabolism-targeting and other therapies would be an attractive perspective for further research. [ABSTRACT FROM AUTHOR]

CpG is a widely used adjuvant that enhances the cellular immune response by entering antigen-presenting cells and binding with receptors. The traditional physical mixing of the antigen and CpG adjuvant results in a low adjuvant utilization rate. Considering the efficient delivery capacity of nanovaccines, we developed an attractive strategy to covalently load CpG onto the nanovaccine, which realized the co-delivery of both CpG and the antigen. Briefly, the azide-modified CpG was conjugated to a bioconjugate nanovaccine (NP-OPS) against Shigella flexneri through a simple two-step reaction. After characterization of the novel vaccine (NP-OPS-CpG), a series of in vitro and in vivo experiments were performed, including in vivo imaging, lymph node sectioning, and dendritic cell stimulation, and the results showed that more CpG reached the lymph nodes after covalent coupling. Subsequent flow cytometry analysis of lymph nodes from immunized mice showed that the cellular immune response was greatly promoted by the nanovaccine coupled with CpG. Moreover, by analyzing the antibody subtypes of immunized mice, NP-OPS-CpG was found to further promote a Th1-biased immune response. Thus, we developed an attractive method to load CpG on a nanovaccine that is simple, convenient, and is especially suitable for immune enhancement of vaccines against intracellular bacteria. [ABSTRACT FROM AUTHOR]

Lactate, once recognized as a wasty product from anaerobic glycolysis, is proved to be a pivotal signal molecule. Lactate accumulation occurs in diverse physiological and pathological settings due to the imbalance between lactate production and clearance. Under the condition with drastic changes in local microenvironment, such as tumorigenesis, inflammation, and microbial infection, the glycolysis turns to be active in surrounding cells leading to increased lactate release. Meanwhile, lactate can be utilized by these cells as an energy substrate and acts as a signal molecule to regulate cell functions through receptor‐dependent or independent pathways. In this review, we tended to tease out the contribution of lactate in tumor progression and immunomodulation. And we also discussed the accessory role of lactate, beyond as the energy source only, in the growth of invading pathogens. [ABSTRACT FROM AUTHOR]