Local Immune Cells Research Articles

Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma.

Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single-cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8+ T cells, a response that was lost upon disease progression. Single-cell RNA-sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.

Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective.

The mononuclear phagocyte system includes monocytes, macrophages, some dendritic cells, and multinuclear giant cells. These cell populations display marked heterogeneity depending on their differentiation from embryonic and bone marrow hematopoietic progenitors, tissue location, and activation. They contribute to tissue homeostasis by interacting with local and systemic immune and non-immune cells through trophic, clearance, and cytocidal functions. During evolution, they contributed to the innate host defense before effector mechanisms of specific adaptive immunity emerged. Mouse macrophages appear at mid-gestation and are distributed throughout the embryo to facilitate organogenesis and clear cells undergoing programmed cell death. Yolk sac, AGM, and fetal liver-derived tissue-resident macrophages persist throughout postnatal and adult life, supplemented by bone marrow-derived blood monocytes, as required after injury and infection. Nobel awards to Elie Metchnikoff and Paul Ehrlich in 1908 drew attention to cellular phagocytic and humoral immunity, respectively. In 2011, prizes were awarded to Jules Hoffmann and Bruce Beutler for contributions to innate immunity and to Ralph Steinman for the discovery of dendritic cells and their role in antigen presentation to T lymphocytes. We trace milestones in the history of mononuclear phagocyte research from the perspective of Nobel awards bearing directly and indirectly on their role in cellular immunity.

Age-dependent changes in phagocytic activity: in vivo response of mouse pulmonary antigen presenting cells to direct lung delivery of charged PEGDA nanoparticles

BackgroundCurrent needle-based vaccination for respiratory viruses is ineffective at producing sufficient, long-lasting local immunity in the elderly. Direct pulmonary delivery to the resident local pulmonary immune cells can create long-term mucosal responses. However, criteria for drug vehicle design rules that can overcome age-specific changes in immune cell functions have yet to be established.ResultsHere, in vivo charge-based nanoparticle (NP) uptake was compared in mice of two age groups (2- and 16-months) within the four notable pulmonary antigen presenting cell (APC) populations: alveolar macrophages (AM), interstitial macrophages (IM), CD103+ dendritic cells (DCs), and CD11b+ DCs. Both macrophage populations exhibited preferential uptake of anionic nanoparticles but showed inverse rates of phagocytosis between the AM and IM populations across age. DC populations demonstrated preferential uptake of cationic nanoparticles, which remarkably did not significantly change in the aged group. Further characterization of cell phenotypes post-NP internalization demonstrated unique surface marker expression and activation levels for each APC population, showcasing heightened DC inflammatory response to NP delivery in the aged group.ConclusionThe age of mice demonstrated significant preferences in the charge-based NP uptake in APCs that differed greatly between macrophages and DCs. Carefully balance of the targeting and activation of specific types of pulmonary APCs will be critical to produce efficient, age-based vaccines for the growing elderly population.Graphical

Effectiveness of 650 nm red laser photobiomodulation therapy to accelerate wound healing post tooth extraction

After tooth extraction, there can be consequences involving injury to the tissue surrounding the extracted tooth, which may lead to severe problems such as inflammation and infection. The wound healing process comprises inflammation, proliferation, and remodeling phases. Photobiomodulation is a therapy form that utilizes the interaction of a light source with tissue. This interaction can activate an increase in Adenosine Triphosphate (ATP), which subsequently triggers a chain reaction leading to the creation of new blood vessels and an increase in the number of fibroblasts. This study used a red laser light source with a power of 3.32 ± 0.01 mW, delivering a dose of 3.5 J to patients for extraction indications. The parameters observed included Interleukin 1_ (IL-1_), Prostaglandin E2 (PGE2), Human Beta defensin 2 (HBD2), and Gingival Index (GI). The results of testing saliva samples using the enzyme-linked immunosorbent test (ELISA) for the parameters IL-1_, PGE2, and HBD2 show a significant influence between the control and therapy groups. Meanwhile, GI revealed a significant influence of therapy on the wound-healing process. Using the Mann-Whitney U test, on day 1, the p-value was found to be 0.32, indicating no significant deference between the control and therapy groups. However, on the third day after the therapy was administered, the p-value was obtained as 0.01, signifying a significant deference between the control and therapy groups. On day 5, a p-value of 0.034 was obtained, signifying a significant deference between the control and therapy groups. Based on the research results, it can be observed that there is a decrease in the values of IL-1_, PGE2, HBD2, and GI. This indicates that local immune cells, including resident macrophages, are activated by pro-inflammatory mediators released in response to injury, and they play an essential role in accelerating wound healing.

The role of HPV11 E7 in modulating STING-dependent interferon β response in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare benign tumor caused mainly by the infection of the respiratory tract epithelial cells by the human papillomavirus (HPV) type 6/11. However, the specific mechanisms underlying the inhibition of the host's innate immune response by HPV remain unclear. For this purpose, we employed single-cell RNA sequencing to analyze the states of various immune cells in RRP samples post-HPV infection and utilized a cellular model of HPV infection to elucidate the mechanisms by which HPV evades the innate immune system in RRP. The results revealed distinct immune cell heterogeneity in RRP and demonstrated that HPV11 E7 can inhibit the phosphorylation of the stimulator of interferon genes protein, thereby circumventing the body's antiviral response. In vitro co-culture experiments demonstrated that stimulation of macrophages to produce interferon-beta induced the death of HPV-infected epithelial cells, also reducing HPV viral levels. In summary, our study preliminarily identifies the potential mechanisms by which HPV evades the host's antiviral immune response, as well as the latent antiviral functions exhibited by activated macrophages. This research serves as an initial exploration of antiviral immune evasion in RRP, laying a solid foundation for investigating immunotherapeutic approaches for the disease.IMPORTANCESurgical tumor reduction is the most common treatment for recurrent respiratory papillomatosis (RRP). One of the characteristics of RRP is its persistent recurrence, and multiple surgeries are usually required to control the symptoms. Recently, some adjuvant therapies have shown effectiveness, but none of them can completely clear human papillomavirus (HPV) infection, and thus, a localized antiviral immune response is significant for disease control; after all, HPV infection is limited to the epithelium. Inhibition of interferon-beta (IFN-β) secretion by HPV11 E7 viral proteins in epithelial cells by affecting stimulator of interferon genes phosphorylation may account for the persistence of low-risk HPV replication in the RRP. Moreover, suppression of the IFN-I pathway in RRP cell types might provide clues regarding the hyporeactive function of local immune cells. However, activation of macrophage groups to produce IFN-β can still destroy HPV-infected cells.

Abstract 1176: Identification of circulating and spatial dynamics of immune cells response to to immune checkpoint inhibitors in triple-negative breast cancer at single-cell resolution

Abstract Background: Triple-negative breast cancer (TNBC) have had significantly worse survival outcome compared to other BC subtypes even though treatment strategies of TNBC have been advanced. The advent of immune checkpoint inhibitors (ICIs), especially pembrolizumab, a PD-1 inhibitor, has started to revolutionize TNBC treatment, showing encouraging effects in improving survival outcomes regardless of treatment settings. In neoadjuvant setting, pembrolizumab with cytotoxic chemotherapy achieved 13.6 % of pathologic complete response rate improvement and 36% of three-year event reduction. Therefore, pembrolizumab has highlighted new dimensions of TNBC's immunogenic characteristics. However, no immunogenic characteristics to predict the response of pembrolizumab have not been revealed. Methods: This study was designed as prospective, translational research for stage II or III TNBC patients scheduled for neoadjuvant chemotherapy with or without pembrolizumab followed by curative surgery. Tissue and blood samples were collected at baseline, 1 or 3 weeks after the first treatment initiation and curative surgery. We employed various single-cell and bulk RNA techniques for our multiomic analysis, including peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing, T cell receptor sequencing (scTCR), high-resolution single-cell spatial transcriptomics (Xenium) targeting 380 genes, and bulk PBMC and tissue TCR analysis Results: From March 2023 to October 2023, 37 patients were enrolled in this study. Of 37 patients, we collected 36 blood and BC tissue samples at baseline, as well as 35 blood and 14 BC tissues at follow-up. These samples were analyzed and also compared with sex and age-matched healthy controls (n = 65). Of 37 patients, two patients were treated with only cytotoxic chemotherapy without pembrolizumab. We observed substantial increases in both systemic and localized immune responses, primarily marked by an upsurge in activated T cells and a decrease in regulatory T cells. A notable rise in TCR diversity post one week of treatment was followed by clonal expansion of activated T cells after three weeks in both blood and tissue. In addition, we observed a significant enrichment of pathways related to inflammatory response in classical monocytes following treatment. Conclusion: The findings from this study significantly enhance our understanding of the dynamics of circulating and local immune cells in TNBC, analyzed at a single-cell level with spatial information. These insights reveal how pembrolizumab alters the immune landscape and correlates these changes with treatment responses. Importantly, the data provide valuable indicators for predicting which TNBC patients are more likely to respond to neoadjuvant pembrolizumab therapy. Citation Format: Eun Seop Seo, Hae Hyun Jung, Kibyung Kim, Kyunghee Park, Eun Young Ko, Byung Joo Chae, Jeong Eon Lee, Eun Yoon Cho, Ji-Yeon Kim, Woong-Yang Park. Identification of circulating and spatial dynamics of immune cells response to to immune checkpoint inhibitors in triple-negative breast cancer at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1176.

Abstract 6347: To develop a tumor selective INF-γ-Yervoy fusion antibody to increase the therapeutic effect and safety of current Yervoy therapy in cancer

Abstract Introduction: Immune checkpoint inhibitor therapy is a highly promising strategy for clinical treatment of cancer. Among these inhibitors, yervoy stands out for its ability to induce cytotoxic T cell proliferation and activation by binding to CTLA-4. However, FDA has reported that yervoy would induce the over-activation of immune cells and cause the serious side effects. In additional, the therapeutic efficacy and application of Yervoy were still limited by the MHC expression of patient's tumor. Strategy: Therefore, we have developed a protease specific pro INF-γ-Yervoy to increase the therapeutic effect and safety of current immune checkpoint blockade therapy in cancer. We used the MMP-2/9 protease substrate as a linker between INF-γ and Yervoy. Using the concept of spatial shielding, IFNγ and Yervoy can block their functions from each other. Once the INF-γ-Yervoy arrives to the tumoral region, the INF-γ-Yervoy will be removed from Hinge Yervoy by the over-expressed MMPs protease locally so that the Yervoy will recruit its binding ability in order to increase the drug selectivity and improve the side effects. The INF-γ also can increase the MHC I expression in tumor to overcome the MHC-limitation of Yervoy. Result: On activation by MMP, IFNγ-yervoy not only restored yervoy’s binding ability but also released biologically active IFNγ. This finding confirms the reliability of IFNγ-yervoy’s functionality. In vivo studies demonstrated that IFNγ-yervoy enhances the therapeutic effect of yervoy against colorectal cancer by increasing CD8+ and CD4+ lymphocyte infiltration into the tumor area and inducing MHC-I expression in tumor cells. Mice treated with IFNγ-yervoy showed higher survival rates and body weight, as well as lower CD4+ and CD8+ lymphocyte activation rates in the blood and reduced organ damage. Conclusion: These results provide strong evidence that tumor-selective IFNγ-yervoy can improve the effectiveness of yervoy while reducing its side effects. It is likely that future immunotherapies would rely on such antibodies to activate local cancer cells or immune cells, thereby increasing the therapeutic effectiveness of cancer treatments and ensuring their safety. Keyword: Immune checkpoint inhibitor therapy, IFNγ, yervoy, rectal cancer, CTLA4 Citation Format: Chih-Hung Chuang. To develop a tumor selective INF-γ-Yervoy fusion antibody to increase the therapeutic effect and safety of current Yervoy therapy in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6347.

Selective activation of IFNγ–ipilimumab enhances the therapeutic effect and safety of ipilimumab

IntroductionImmune checkpoint inhibitor therapy is a highly promising strategy for clinical treatment of cancer. Among these inhibitors, ipilimumab stands out for its ability to induce cytotoxic T cell proliferation and activation by binding to CTLA-4. However, ipilimumab also gives rise to systemic immune-related adverse effects and tumor immune evasion, limiting its effectiveness. ObjectivesWe developed IFNγ–ipilimumab and confirmed that the addition of INF-γ does not alter the fundamental properties of ipilimumab. ResultsIFNγ–ipilimumab can be activated by matrix metalloproteinases, thereby promoting the IFNγ signaling pathway and enhancing the cytotoxicity of T cells. In vivo studies demonstrated that IFNγ–ipilimumab enhances the therapeutic effect of ipilimumab against colorectal cancer by increasing CD8+ and CD4+ lymphocyte infiltration into the tumor area and inducing MHC-I expression in tumor cells. Mice treated with IFNγ–ipilimumab showed higher survival rates and body weight, as well as lower CD4+ and CD8+ lymphocyte activation rates in the blood and reduced organ damage. ConclusionIFNγ–ipilimumab improved the effectiveness of ipilimumab while reducing its side effects. It is likely that future immunotherapies would rely on such antibodies to activate local cancer cells or immune cells, thereby increasing the therapeutic effectiveness of cancer treatments and ensuring their safety.

CD8+ Tissue-Resident Memory T Cells: Versatile Guardians of the Tissue.

Tissue-resident memory T (Trm) cells are a subset of T cells maintained throughout life within nonlymphoid tissues without significant contribution from circulating memory T cells. CD8+ Trm cells contribute to both tissue surveillance and direct elimination of pathogens through a variety of mechanisms. Reactivation of these Trm cells during infection drives systematic changes within the tissue, including altering the state of the epithelium, activating local immune cells, and contributing to the permissiveness of the tissue for circulating immune cell entry. Trm cells can be further classified by their functional outputs, which can be either subset- or tissue-specific, and include proliferation, tissue egress, and modulation of tissue physiology. These functional outputs of Trm cells are linked to the heterogeneity and plasticity of this population, and uncovering the unique responses of different Trm cell subsets and their role in immunity will allow us to modulate Trm cell responses for optimal control of disease.

Interferon-epsilon is a novel regulator of NK cell responses in the uterus

The uterus is a unique mucosal site where immune responses are balanced to be permissive of a fetus, yet protective against infections. Regulation of natural killer (NK) cell responses in the uterus during infection is critical, yet no studies have identified uterine-specific factors that control NK cell responses in this immune-privileged site. We show that the constitutive expression of IFNε in the uterus plays a crucial role in promoting the accumulation, activation, and IFNγ production of NK cells in uterine tissue during Chlamydia infection. Uterine epithelial IFNε primes NK cell responses indirectly by increasing IL-15 production by local immune cells and directly by promoting the accumulation of a pre-pro-like NK cell progenitor population and activation of NK cells in the uterus. These findings demonstrate the unique features of this uterine-specific type I IFN and the mechanisms that underpin its major role in orchestrating innate immune cell protection against uterine infection.

Rapamycin can alleviate the submandibular gland pathology of Sjögren's syndrome by limiting the activation of cGAS-STING signaling pathway.

Sjögren's Syndrome (SS) is also known as autoimmune exocrine gland disease. Previous studies have confirmed that adaptive immunity plays an important role in the development of this disease. But less is known about the role of the innate immune system. To identify the core pathways, and local infiltrated immune cells in the local immune microenvironment of SS. We verified the activation of these core genes and core signaling pathways in SS model mice by in vivo experiment and transcriptome sequencing. Finally, we identified 6 core genes EPSTI1, IFI44L, MX1, CXCL10, IFIT3, and IFI44. All the 6 genes had good diagnostic value. Based on multi-omics sequencing results and experimental studies, we found that cGAS-STING signaling pathway is most relevant to the pathogenesis of SS. By in vivo experiments, we verified that autophagy is the key brake to limit the activation of cGAS-STING signaling pathway. Maladaptive activation of autophagy and cGAS-STING signaling pathway are central contributors to the SG pathogenesis of pSS patient. Regulating autophagy by rapamycin may be a possible treatment for Sjögren's syndrome in the future.

Unmasking Chemokine-Inducing Specificity in Oligosaccharide Biomaterial to Promote Hair Growth.

Hair loss affects over 50 million people worldwide with limited therapeutic options. Despite evidence highlighting the vital role of local immune cells in regulating the life cycle of hair follicles (HFs), accurate regulation of immunocytes to directly promote hair growth remains unachieved. Here, inspired by the physiological feedback in the skin immunity to suppress microbe-triggered inflammation, an oligosaccharide biomaterial with "unmasked" specific activity is developed to recruit regulatory T (Treg ) cells around HFs, leading to accelerated hair growth in mice. By processing the glucomannan polysaccharide via controllable enzymatic cleavage, a series of oligosaccharide fractions with more specific chemokine-inducing functions is obtained. Notably, a hexasaccharide-based fraction (OG6) stimulates macrophages to selectively express Treg -chemoattractant C-C Motif Chemokine Ligand 5 (CCL5) through a mannose receptor-mediated endocytosis and NOD1/2-dependent signaling, as evidenced by molecular docking, inhibition assays, and a Foxp3-reporter mouse model. Intradermal delivery of OG6 to the depilated mouse skin promotes Treg mobilization around HFs and stimulates de novo regeneration of robust hairs. This study demonstrates that unmasking precise immunomodulatory functions in oligosaccharides from their parental polysaccharide can potentially solve the long-lasting dilemma with polysaccharide biomaterials that are widely renowned for versatile activities yet high heterogeneity, opening new avenues to designing glycan-based therapeutic tools with improved specificity and safety.

Advances in the research of exosomes in renal cell carcinoma: from mechanisms to applications.

Renal cell carcinoma (RCC) is one of the most malignant urological tumors. Currently, there is a lack of molecular markers for early diagnosis of RCC. The 5-year survival rate for early-stage RCC is generally favorable; however, the prognosis takes a significant downturn when the tumor progresses to distant metastasis. Therefore, the identification of molecular markers for RCC is crucial in enhancing early diagnosis rates. Exosomes are a type of extracellular vesicle (EV) typically ranging in size from 30 nm to 150 nm, which contain RNA, DNA, proteins, lipids, etc. They can impact neighboring receptor cells through the autocrine or paracrine pathway, influence cellular communication, and regulate the local immune cells, consequently shaping the tumor immune microenvironment and closely associating with tumor development. The clinical application of exosomes as tumor markers and therapeutic targets has ignited significant interest within the research community. This review aims to provide a comprehensive summary of the advancements in exosome research within the context of RCC.

The expression of nicotinic acetylcholine receptor subunits and their associations with local immune cells and prognosis in oral squamous cell carcinoma.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that may be responsible for cancer cell proliferation, epithelial-mesenchymal transition (EMT), and immune regulation. However, little is known about the associations of different nAChR subunits with tumor microenvironment in oral squamous cell carcinoma (OSCC). We retrospectively reviewed pathology samples from 75 OSCC patients by immunohistochemistry. In addition, a cohort of 307 OSCC patients in The Cancer Genome Atlas was analyzed. Subunit α1 was specific to peri-OSCC skeletal muscle. Increased α1 was associated with increased CD44 (cancer stem cells), increased CD3 and 8 (T cells), increased CD56 and 16 (natural killer cells), a decreased T stage, and an increased N stage. Increased α3 was associated with increased CD56 and 16. Increased α5 was associated with decreased CD3, 8, and 56, a decreased T stage, an increased N stage, worse survival, and decreased epithelial features. Increased α7 was associated with increased CD3, 8, 56, and 16, decreased tumor/peritumor ratios of CD3, 8, and 56 immune cells, and increased epithelial features. Increased local immune cells were associated with a better prognosis. α5 is the only subunit associated with decreased local immune cells and worse survival, while α1, α3, and α7 are associated with increased local immune cells in OSCC. α5 and α7 are correlated with different EMT states to be mesenchymal-like and epithelial-like OSCC, respectively. Protein expression data of the nAChR subunits, complementary to gene expression data, could provide meaningful information regarding the EMT status of OSCC associated with immune responses and prognosis.

Interferon inhibits the release of herpes simplex virus-1 from the axons of sensory neurons.

Herpes simplex virus-1 (HSV-1) is a human pathogen known to cause cold sores and genital herpes. HSV-1 establishes lifelong infections in our sensory neurons, with no cure or vaccine available. HSV-1 can reactivate sporadically and travel back along sensory nerves, where it can form lesions in the oral and genital mucosa, eye, and skin, or be shed asymptomatically. New treatment options are needed as resistance is emerging to current antiviral therapies. Here, we show that interferons (IFNs) are capable of blocking virus release from nerve endings, potentially stopping HSV-1 transmission into the skin. Furthermore, we show that IFNγ has the potential to have widespread antiviral effects in the neuron and may have additional effects on HSV-1 reactivation. Together, this study identifies new targets for the development of immunotherapies to stop the spread of HSV-1 from the nerves into the skin.

Cancer Immunotherapy Using Bioengineered Micro/Nano Structured Hydrogels.

Hydrogels, a class of materials with a 3Dnetwork structure, are widely used in various applications of therapeutic delivery, particularly cancer therapy. Micro and nanogels as miniaturized structures of the bioengineered hydrogels may provide extensive benefits over the common hydrogels in encapsulation and controlled release of small molecular drugs, macromolecular therapeutics, and even cells. Cancer immunotherapy is rapidly developing, and micro/nanostructured hydrogels have gained wide attention regarding their engineered payload release properties that enhance systemic anticancer immunity. Additionally, they are a great candidate due to their local administration properties with a focus on local immune cell manipulation in favor of active and passive immunotherapies. Although applied locally, such micro/nanostructured can also activate systemic antitumor immune responses by releasing nanovaccines safely and effectively inhibiting tumor metastasis and recurrence. However, such hydrogels are mostly used as locally administered carriers to stimulate the immune cells by releasing tumor lysate, drugs, or nanovaccines. In this review, the latest developments in cancer immunotherapy are summarized using micro/nanostructured hydrogels with a particular emphasis on their function depending on the administration route. Moreover, the potential for clinical translation of these hydrogel-based cancer immunotherapies is also discussed.

TERT mutations-associated alterations in clinical characteristics, immune environment and therapy response in glioblastomas

Objective TERTis the most frequently mutated gene in adult glioblastomas (GBMs) defined by the 2021 World Health Organization classification system. The present study aims to explore differences in clinical characteristics and immune microenvironment between TERT mutant and wild-type GBM.MethodsThree GBM-related cohorts consisting of 205 GBM patients in our cohort, 463 GBM patients without immune checkpoint inhibitor(ICI) therapy and 1465 tumour patients (including 92 GBM cases) receiving ICI treatment in the MSK cohort were included. Retrospective analysis and immunohistochemistry assay were used for investigating the local (including tumour cells, local immune cells, and seizures) and systemic (including circulating immune cells, coagulation-related functions, and prognosis) effects of TERT mutations. Besides, differences in genetic alterations and immunotherapy responses between TERT mutant and wild-type GBMs were also explored.ResultsWe found that TERT mutant and wild-type GBMs possessed similar initial clinic symptoms, circulating immune microenvironment and immunotherapy response. With respect to that in TERT wild-type GBMs, mutations in TERT resulted in higher levels of tumour-infiltrating neutrophils, prolonged coagulation time, worse chemotherapy response and poorer overall survival.ConclusionMutations in TERT alter the local immune environment and decrease the sensitivity of GBM to chemotherapy.

Recruited macrophages elicit atrial fibrillation.

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2-∕- HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.

Crosstalk between the Resident Microbiota and the Immune Cells Regulates Female Genital Tract Health.

The female genital tract (FGT) performs several functions related to reproduction, but due to its direct exposure to the external environment, it may suffer microbial infections. Both the upper (uterus and cervix) and lower (vagina) FGT are covered by an epithelium, and contain immune cells (macrophages, dendritic cells, T and B lymphocytes) that afford a robust protection to the host. Its upper and the lower part differ in terms of Lactobacillus spp., which are dominant in the vagina. An alteration of the physiological equilibrium between the local microbiota and immune cells leads to a condition of dysbiosis which, in turn, may account for the outcome of FGT infection. Aerobic vaginitis, bacterial vaginosis, and Chlamydia trachomatis are the most frequent infections, and can lead to severe complications in reproduction and pregnancy. The use of natural products, such as probiotics, polyphenols, and lactoferrin in the course of FGT infections is an issue of current investigation. In spite of positive results, more research is needed to define the most appropriate administration, according to the type of patient.

Innate immune activation and modulatory factors of Helicobacter pylori towards phagocytic and nonphagocytic cells.

Helicobacter pylori is an intriguing obligate host-associated human pathogen with a specific host interaction biology, which has been shaped by thousands of years of host-pathogen coevolution. Molecular mechanisms of interaction of H. pylori with the local immune cells in the human system are less well defined than epithelial cell interactions, although various myeloid cells, including neutrophils and other phagocytes, are locally present or attracted to the sites of infection and interact with H. pylori. We have recently addressed the question of novel bacterial innate immune stimuli, including bacterial cell envelope metabolites, that can activate and modulate cell responses via the H. pylori Cag type IV secretion system. This review article gives an overview of what is currently known about the interaction modes and mechanisms of H. pylori with diverse human cell types, with a focus on bacterial metabolites and cells of the myeloid lineage including phagocytic and antigen-presenting cells.