Innate Immune Cells Research Articles

Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy.

Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor β (TGFβ) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance.

A zebrafish xenotransplant model of anaplastic thyroid cancer to study tumor microenvironment and innate immune cell interactions in vivo.

Anaplastic thyroid cancer (ATC) is of the most aggressive thyroid cancer. While ATC is rare, it accounts for a disproportionately high number of thyroid cancer-related deaths. Here, we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo. Using both mouse (T4888M) and human (C643)-derived fluorescently labeled ATC cell lines, we show these cell lines display different engraftment rates, mass volume, proliferation, cell death, angiogenic potential, and neutrophil and macrophage recruitment and infiltration. Next, using a PIP-FUCCI reporter to track proliferation in vivo, we observed cells in each phase of the cell cycle. Additionally, we performed long-term non-invasive intravital microscopy over 48 h to understand cellular dynamics in the tumor microenvironment at the single-cell level. Lastly, we tested two drug treatments, AZD2014 and a combination therapy of dabrafenib and trametinib, to show our model could be used as an effective screening platform for new therapeutic compounds for ATC. Altogether, we show that zebrafish xenotransplants make a great model to study thyroid carcinogenesis and the tumor microenvironment, while also being a suitable model to test new therapeutics in vivo.

Calcineurin-NFAT signaling controls neutrophils´ ability of chemoattraction upon fungal infection.

Calcineurin - nuclear factor of activated T-cell (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression but besides their required T-cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitors-treated patients to opportunistic fungal infections. Neutrophils play an essential role in innate immunity as a defense against pathogens, however, the effect of CN-NFAT inhibitors on neutrophil function was poorly described. Thus, we tested the response of human neutrophils to opportunistic fungal pathogens, namely Candida albicans and Aspergillus fumigatus in the presence of CN-NFAT inhibitors. Here, we report that the NFAT pathway members were expressed in neutrophils and mediated part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes with subsequent production of effector molecules. Importantly, genes and proteins involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2, CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.

Medicinal and immunological aspects of bacteriophage therapy to combat antibiotic resistance

Bacteriophages are viruses that infect bacterial cells and use their machinery to reproduce. This unique characteristic holds immense promise for combating antibiotic-resistant bacterial infections, a growing global threat. There are two types: one of them is named temperate phages, which inject their genomic material into bacteria and integrate into the host’s genome, while the second one is entitled as lytic phages that subdue the entire metabolism of the bacterium for the synthesis of its genome and proteins, including lytic proteins involved in breaking bacterial cell membrane and release of novel phages. In addition, phage therapy can be expressed through anti-biofilm activity and by triggering innate and adaptive immune cells responses. Moreover, no adverse effects of phage therapy have been reported. However, phage therapy is still grim for many and could influence some interpretations related to immune response, bacteriophage selections, and phage resistance in the future.

Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer.

Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease. 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter. Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1+ expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4+, CD8+, and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells. LvMs are less likely to express PD-L1+ tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.

Single-Cell Informatics for Tumor Microenvironment and Immunotherapy.

Cancer comprises malignant cells surrounded by the tumor microenvironment (TME), a dynamic ecosystem composed of heterogeneous cell populations that exert unique influences on tumor development. The immune community within the TME plays a substantial role in tumorigenesis and tumor evolution. The innate and adaptive immune cells "talk" to the tumor through ligand-receptor interactions and signaling molecules, forming a complex communication network to influence the cellular and molecular basis of cancer. Such intricate intratumoral immune composition and interactions foster the application of immunotherapies, which empower the immune system against cancer to elicit durable long-term responses in cancer patients. Single-cell technologies have allowed for the dissection and characterization of the TME to an unprecedented level, while recent advancements in bioinformatics tools have expanded the horizon and depth of high-dimensional single-cell data analysis. This review will unravel the intertwined networks between malignancy and immunity, explore the utilization of computational tools for a deeper understanding of tumor-immune communications, and discuss the application of these approaches to aid in diagnosis or treatment decision making in the clinical setting, as well as the current challenges faced by the researchers with their potential future improvements.

Effect of F-isoprostane class on cow peripheral blood neutrophil microbicidal function in vitro

Isoprostanes (isoP) are formed during conditions of oxidative stress (OS) through the oxidation of cell membrane fatty acids. Different classes of isoP are formed depending on the fatty acid being oxidized but the biological activity of these molecules in innate immune cells is poorly understood. Thus, the objective of this study was to compare in vitro the effects of F2- and F3-isoP on neutrophil microbicidal functions. We isolated neutrophils from 6 dairy cows and incubated them for 8 h at various concentrations of F2- and F3-isoP. Then, microbicidal function was assessed in terms of phagocytosis, respiratory burst, myeloperoxidase activity, and extracellular trap formation. In vitro supplementation with F3-isoP enhanced microbicidal capabilities whereas supplementation with F2-isoP decreased or did not impact these microbe killing functions. Hence, favoring the production of F3- over F2-isoprostanes may be a strategy to augment neutrophils’ functional capacity during OS conditions. This should be tested in vivo.

Lipoarabinomannan modification as a source of phenotypic heterogeneity in host-adapted Mycobacterium abscessus isolates

Mycobacterium abscessus is increasingly recognized as the causative agent of chronic pulmonary infections in humans. One of the genes found to be under strong evolutionary pressure during adaptation of M. abscessus to the human lung is embC which encodes an arabinosyltransferase required for the biosynthesis of the cell envelope lipoglycan, lipoarabinomannan (LAM). To assess the impact of patient-derived embC mutations on the physiology and virulence of M. abscessus, mutations were introduced in the isogenic background of M. abscessus ATCC 19977 and the resulting strains probed for phenotypic changes in a variety of in vitro and host cell-based assays relevant to infection. We show that patient-derived mutational variations in EmbC result in an unexpectedly large number of changes in the physiology of M. abscessus, and its interactions with innate immune cells. Not only did the mutants produce previously unknown forms of LAM with a truncated arabinan domain and 3-linked oligomannoside chains, they also displayed significantly altered cording, sliding motility, and biofilm-forming capacities. The mutants further differed from wild-type M. abscessus in their ability to replicate and induce inflammatory responses in human monocyte-derived macrophages and epithelial cells. The fact that different embC mutations were associated with distinct physiologic and pathogenic outcomes indicates that structural alterations in LAM caused by nonsynonymous nucleotide polymorphisms in embC may be a rapid, one-step, way for M. abscessus to generate broad-spectrum diversity beneficial to survival within the heterogeneous and constantly evolving environment of the infected human airway.

The potency of hematopoietic stem cell reprogramming for changing immune tone.

Innate immune memory endows innate immune cells with antigen independent heightened responsiveness to subsequent challenges. The durability of this response can be mediated by inflammation induced epigenetic and metabolic reprogramming in hematopoietic stem and progenitor cells (HSPCs) that are maintained through differentiation to mature immune progeny. Understanding the mechanisms and extent of trained immunity induction by pathogens and vaccines, such as BCG, in HSPC remains a critical area of exploration with important implications for health and disease. Here we review these concepts and present new analysis to highlight how inflammatory reprogramming of HSPC can potently alter immune tone, including to enhance specific anti-tumor responses. New findings in the field pave the way for novel HSPC targeting therapeutic strategies in cancer and other contexts of immune modulation. Future studies are expected to unravel diverse and extensive effects of infections, vaccines, microbiota, and sterile inflammation on hematopoietic progenitor cells and begin to illuminate the broad spectrum of immunologic tuning that can be established through altering HSPC phenotypes. The purpose of this review is to draw attention to emerging and speculative topics in this field where we posit that focused study of HSPC in the framework of trained immunity holds significant promise.

In situ administration of STING-activating hyaluronic acid conjugate primes anti-glioblastoma immune response

Glioblastoma (GBM) is an aggressive brain tumor, with a highly immunosuppressive tumor immune microenvironment (TIME). In this work, we investigated the use of the STimulator of INterferon Genes (STING) pathway as an effective means to remodel the GBM TIME through the recruitment of both innate and adaptive immune cell populations. Using hyaluronic acid (HA), we developed a novel polymer-drug conjugate of a non-nucleotide STING agonist (MSA2), called HA-MSA2 for the in situ treatment of GBM. In JAWSII cells, HA-MSA2 exerted a greater increase of STING signaling and upregulation of STING-related downstream cyto-/chemokines in immune cells than the free drug. HA-MSA2 also elicited cancer cell-intrinsic immunostimulatory gene expression and promoted immunogenic cell death of GBM cells. In the SB28 GBM model, local delivery of HA-MSA2 induced a delay in tumor growth and a significant extension of survival. The analysis of the TIME showed a profound shift in the GBM immune landscape after HA-MSA2 treatment, with higher infiltration by innate and adaptive immune cells including dendritic, natural killer (NK) and CD8 T cell populations. The therapeutic potential of this novel polymer conjugate warrants further investigation, particularly with other chemo-immunotherapeutics or cancer vaccines as a promising combinatorial therapeutic approach.

Identification and immunological characteristics of anoikis-associated molecular clusters in lung adenocarcinoma

Anoikis plays a crucial role in the progression, prognosis, and immune response of lung adenocarcinoma (LUAD). However, its specific impact on LUAD remains unclear. In this study, we investigated the intricate interplay of nesting apoptotic factors in LUAD. By analyzing nine key nesting apoptotic factors, we categorized LUAD patients into two distinct clusters. Further examination of immune cell profiles revealed that Cluster A exhibited greater infiltration of innate immune cells than did Cluster B. Additionally, we identified two genes closely associated with prognosis and developed a predictive model to differentiate patients based on molecular clusters. Our findings suggest that the loss of specific anoikis-related genes could significantly influence the prognosis, tumor microenvironment, and clinical features of LUAD patients. Furthermore, we validated the expression and functional roles of two pivotal prognostic genes, solute carrier family 2 member 1 (SLC2A1) and sphingosine kinase 1 (SPHK1), in regulating tumor cell viability, migration, apoptosis, and anoikis. These results offer valuable insights for future mechanistic investigations. In conclusion, this study provides new avenues for advancing our understanding of LUAD, improving prognostic assessments, and developing more effective immunotherapy strategies.

Spatial distribution of tumor-associated macrophages in an orthotopic prostate cancer mouse model.

Mounting evidence suggests that the immune landscape within prostate tumors influences progression, metastasis, treatment response, and patient outcomes. In this study, we investigated the spatial density of innate immune cell populations within NOD.SCID orthotopic prostate cancer xenografts following microinjection of human DU145 prostate cancer cells. Our laboratory has previously developed nanoscale liposomes that attach to leukocytes via conjugated E-selectin (ES) and kill cancer cells via TNF-related apoptosis inducing ligand (TRAIL). Immunohistochemistry (IHC) staining was performed on tumor samples to identify and quantify leukocyte infiltration for different periods of tumor growth and E-selectin/TRAIL (EST) liposome treatments. We examined the spatial-temporal dynamics of three different immune cell types infiltrating tumors using QuPath image analysis software. IHC staining revealed that F4/80+ tumor-associated macrophages (TAMs) were the most abundant immune cells in all groups, irrespective of time or treatment. The density of TAMs decreased over the course of tumor growth and decreased in response to EST liposome treatments. Intratumoral versus marginal analysis showed a greater presence of TAMs in the marginal regions at 3 weeks of tumor growth which became more evenly distributed over time and in tumors treated with EST liposomes. TUNEL staining indicated that EST liposomes significantly increased cell apoptosis in treated tumors. Additionally, confocal microscopy identified liposome-coated TAMs in both the core and periphery of tumors, highlighting the ability of liposomes to infiltrate tumors by "piggybacking" on macrophages. The results of this study indicate that TAMs represent the majority of innate immune cells within NOD.SCID orthotopic prostate tumors, and spatial density varies widely as a function of tumor size, duration of tumor growth, and treatment of EST liposomes.

The unique interplay between antinuclear antibodies and nuclear molecules in the pathogenesis of SLE.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that primarily affects young women and causes a wide range of inflammatory manifestations. The hallmark of SLE is the production of antibodies to components of the cell nucleus (antinuclear antibodies or ANAs). These antibodies can bind to DNA, RNA and protein complexes with nucleic acids. Among ANAs, antibodies to DNA (anti-DNA) are markers for classification and disease activity, waxing and waning in many patients. In the blood, anti-DNA antibodies can bind DNA to form immune complexes with two distinct roles in pathogenesis: renal deposition to provoke nephritis and stimulation of cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors. These sensors are part of an internal host defense system in the cell cytoplasm that can respond to DNA from infecting organisms; during cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors. The formation of immune complexes requires a source of extracellular DNA in an immunologically accessible form. As shown in in vivo and in vitro systems, extracellular DNA can emerge from dead and dying cells in both a free and particulate form. Neutrophils undergoing the process of NETosis can release DNA in mesh-like structures called NETs (neutrophil extracellular traps). In SLE, therefore, the combination of ANAs and immunologically active DNA can create new structures which can promote inflammation throughout the body as well as drive organ inflammation and damage.

Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation

BackgroundTraumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration post-TBI is not fully understood, highlighting a critical gap in our comprehension of TBI pathology and its connection to innate immune activation.MethodsWe combined vascular casting with 3D imaging of solvent-cleared organs (uDISCO) to study the spatial distribution of the blood coagulation protein fibrinogen in large, intact brain volumes and assessed the temporal regulation of the fibrin(ogen) deposition by immunohistochemistry in a murine model of TBI. Fibrin(ogen) deposition and innate immune cell markers were co-localized by immunohistochemistry in mouse and human brains after TBI. We assessed the role of fibrinogen in TBI using unbiased transcriptomics, flow cytometry and immunohistochemistry for innate immune and neuronal markers in Fggγ390–396A knock-in mice, which express a mutant fibrinogen that retains normal clotting function, but lacks the γ390–396 binding motif to CD11b/CD18 integrin receptor.ResultsWe show that cerebral fibrinogen deposits were associated with activated innate immune cells in both human and murine TBI. Genetic elimination of fibrin-CD11b interaction reduced peripheral monocyte recruitment and the activation of inflammatory and reactive oxygen species (ROS) gene pathways in microglia and macrophages after TBI. Blockade of the fibrin-CD11b interaction was also protective from oxidative stress damage and cortical loss after TBI.ConclusionsThese data suggest that fibrinogen is a regulator of innate immune activation and neurodegeneration in TBI. Abrogating post-injury neuroinflammation by selective blockade of fibrin’s inflammatory functions may have implications for long-term neurologic recovery following brain trauma.

CD200 is overexpressed in the pancreatic tumor microenvironment and predictive of overall survival

Pancreatic cancer is an aggressive disease with a 5 year survival rate of 13%. This poor survival is attributed, in part, to limited and ineffective treatments for patients with metastatic disease, highlighting a need to identify molecular drivers of pancreatic cancer to target for more effective treatment. CD200 is a glycoprotein that interacts with the receptor CD200R and elicits an immunosuppressive response. Overexpression of CD200 has been associated with differential outcomes, depending on the tumor type. In the context of pancreatic cancer, we have previously reported that CD200 is expressed in the pancreatic tumor microenvironment (TME), and that targeting CD200 in murine tumor models reduces tumor burden. We hypothesized that CD200 is overexpressed on tumor and stromal populations in the pancreatic TME and that circulating levels of soluble CD200 (sCD200) have prognostic value for overall survival. We discovered that CD200 was overexpressed on immune, stromal, and tumor populations in the pancreatic TME. Particularly, single-cell RNA-sequencing indicated that CD200 was upregulated on inflammatory cancer-associated fibroblasts. Cytometry by time of flight analysis of PBMCs indicated that CD200 was overexpressed on innate immune populations, including monocytes, dendritic cells, and monocytic myeloid-derived suppressor cells. High sCD200 levels in plasma correlated with significantly worse overall and progression-free survival. Additionally, sCD200 correlated with the ratio of circulating matrix metalloproteinase (MMP) 3: tissue inhibitor of metalloproteinase (TIMP) 3 and MMP11/TIMP3. This study highlights the importance of CD200 expression in pancreatic cancer and provides the rationale for designing novel therapeutic strategies that target this protein.

Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to Burkholderia pseudomallei, a lung-tropic pathogen.

Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen Burkholderia pseudomallei. The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in B. pseudomallei infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of B. pseudomallei infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that B. pseudomallei infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that B. pseudomallei likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of B. pseudomallei are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to B. pseudomallei is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to B. pseudomallei infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.

Comprehensive Proteomic Profiling of Aqueous Humor in Idiopathic Uveitis and Vogt-Koyanagi-Harada Syndrome.

Idiopathic uveitis (IU) and Vogt-Koyanagi-Harada (VKH) syndrome are common types of uveitis. However, the exact pathological mechanisms of IU and VKH remain unclear. Proteomic analysis of aqueous humor (AH), the most easily accessible intraocular fluid and a key site of uveitis development, may reveal potential biomarkers and elucidate uveitis pathogenesis. In this study, 44 AH samples, including 12 IU cases, 16 VKH cases, and 16 controls, were subjected to label-free quantitative proteomic analysis. We identified 557 proteins from a comprehensive spectral library of 634 proteins across all samples. The AH proteomic profiles of the IU and VKH groups were different from those of the control group. Differential analysis revealed a shared pattern of extracellular matrix disruption and downregulation of retinal cellular proteins in the IU and VKH groups. Enrichment analysis revealed a protein composition indicative of inflammation in the AH of the IU and VKH groups but not in that of the control group. In the IU and VKH groups, innate immunity played an important role, as indicated by complement cascade activation and overexpression of innate immune cell markers. Extreme gradient boosting (XGBoost), an efficient and robust machine learning algorithm, was subsequently used to screen potential biomarkers for classifying the IU, VKH, and control groups. Transferrin and complement factor B were deemed the most important and represent a promising biomarker panel. These proteins were validated by high-resolution multiple reaction monitoring (HR-MRM) in an independent validation cohort. A classification decision tree was subsequently built for the diagnosis. Our findings further the understanding of the underlying molecular mechanisms in IU and VKH and facilitate the development of potential therapeutic and diagnostic strategies.

Immune drivers of physiological and pathological pain.

Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon. Here, we discuss recent findings on how immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. We also discuss how both innate and adaptive immune cells, by releasing various ligands and mediators, contribute to the initiation, modulation, persistence, or resolution of various modalities of pain. Finally, we propose that the neuroimmune axis is an attractive target for pain treatment, but the challenges in objectively quantifying pain preclinically, variable sex differences in pain presentation, as well as adverse outcomes associated with immune system modulation, all need to be considered in the development of immunotherapies against pain.

Exploring Microbial Metabolite Receptors in Inflammatory Bowel Disease: An In Silico Analysis of Their Potential Role in Inflammation and Fibrosis.

Metabolites produced by dysbiotic intestinal microbiota can influence disease pathophysiology by participating in ligand-receptor interactions. Our aim was to investigate the differential expression of metabolite receptor (MR) genes between inflammatory bowel disease (IBD), healthy individuals (HIs), and disease controls in order to identify possible interactions with inflammatory and fibrotic pathways in the intestine. RNA-sequencing datasets containing 643 Crohn's disease (CD) patients, 467 ulcerative colitis (UC) patients and 295 HIs, and 4 Campylobacter jejuni-infected individuals were retrieved from the Sequence Read Archive, and differential expression was performed using the RaNA-seq online platform. The identified differentially expressed MR genes were used for correlation analysis with up- and downregulated genes in IBD, as well as functional enrichment analysis using a R based pipeline. Overall, 15 MR genes exhibited dysregulated expression in IBD. In inflamed CD, the hydroxycarboxylic acid receptors 2 and 3 (HCAR2, HCAR3) were upregulated and were associated with the recruitment of innate immune cells, while, in the non-inflamed CD ileum, the cannabinoid receptor 1 (CNR1) and the sphingosine-1-phospate receptor 4 (S1PR4) were downregulated and were involved in the regulation of B-cell activation. In inflamed UC, the upregulated receptors HCAR2 and HCAR3 were more closely associated with the process of TH-17 cell differentiation, while the pregnane X receptor (NR1I2) and the transient receptor potential vanilloid 1 (TRPV1) were downregulated and were involved in epithelial barrier maintenance. Our results elucidate the landscape of metabolite receptor expression in IBD, highlighting associations with disease-related functions that could guide the development of new targeted therapies.

CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has transformed cancer immunotherapy. However, significant challenges limit its application beyond B cell-driven malignancies, including limited clinical efficacy, high toxicity, and complex autologous cell product manufacturing. Despite efforts to improve CAR T cell therapy outcomes, there is a growing interest in utilizing alternative immune cells to develop CAR cells. These immune cells offer several advantages, such as major histocompatibility complex (MHC)-independent function, tumor microenvironment (TME) modulation, and increased tissue infiltration capabilities. Currently, CAR products from various T cell subtypes, innate immune cells, hematopoietic progenitor cells, and even exosomes are being explored. These CAR products often show enhanced antitumor efficacy, diminished toxicity, and superior tumor penetration. With these benefits in mind, numerous clinical trials are underway to access the potential of these innovative CAR cells. This review aims to thoroughly examine the advantages, challenges, and existing insights on these new CAR products in cancer treatment.