Local Immune Response Research Articles

Understanding EBV infection and EBV-associated lymphomas in children.

Understanding EBV infection and EBV-associated lymphomas in children.

Dual therapy for amanita phalloides-induced acute liver failure in mice: A combination of etanercept and alpha-1 antitrypsin.

Dual therapy for amanita phalloides-induced acute liver failure in mice: A combination of etanercept and alpha-1 antitrypsin.

PcrV in an intranasal adjuvanted tobacco mosaic virus conjugate vaccine mediates protection from Pseudomonas aeruginosa via an early Th1/Th17 skewed localized and systemic immune response.

PcrV in an intranasal adjuvanted tobacco mosaic virus conjugate vaccine mediates protection from Pseudomonas aeruginosa via an early Th1/Th17 skewed localized and systemic immune response.

Psychological Stress-Induced Local Immune Response to Food Antigens Increases Pain Signaling Across the Gut in Mice.

Psychological Stress-Induced Local Immune Response to Food Antigens Increases Pain Signaling Across the Gut in Mice.

Tertiary lymphoid structures achieve 'cold' to 'hot' transition by remodeling the cold tumor microenvironment.

Tertiary lymphoid structures achieve 'cold' to 'hot' transition by remodeling the cold tumor microenvironment.

OncoBiome: The Emerging Frontier in Cancer-Microbiome Interactions

OncoBiome represents the complex interplay between the human microbiome and cancer biology—a rapidly evolving field investigating how microbial communities influence cancer development, progression, treatment efficacy, and patient outcomes. This bidirectional relationship encompasses multiple dimensions of host-microbe interactions across various body sites and cancer types. Key mechanistic pathways by which the microbiome can influence carcinogenesis involve direct genotoxicity, chronic inflammation leading to persistent microbial dysbiosis, which can create pro-inflammatory environments conducive to cancer development (e.g., H. pylori in gastric cancer, Fusobacterium nucleatum in colorectal cancer). Metabolic modulation involving microbial metabolites like short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide can influence cellular proliferation, apoptosis, and immune function. Further, microbiome composition shapes local and systemic immune responses, potentially affecting immune surveillance of cancer cells. Future research directions include investigating the microbiome's role in Cancer prevention strategies, enhancing immunotherapy response, reducing treatment-related toxicities, developing novel microbiome-based therapeutics, and mitigating cancer recurrence. The OncoBiome represents a promising frontier in precision oncology, potentially offering new insights for cancer prevention, diagnosis, and treatment through the lens of the human microbiome.

Association of Helicobacter pylori with Serum HIF-1α, HIF-2α, and Human Transmembrane Prolyl 4-Hydroxylase Activity in Patients with Chronic Gastritis

Background and Objectives: Chronic mucosal infection with Helicobacter pylori (H. pylori) plays a key role in the development of gastroduodenal disorders such as chronic gastritis, peptic ulcers, gastric lymphoma, and gastric cancer by triggering local immune responses and inducing hypoxic and inflammatory conditions in the gastric mucosa. This study aims to evaluate the potential diagnostic value of hypoxia-inducible factors HIF-1α and HIF-2α, along with transmembrane prolyl 4-hydroxylase (P4H-TM), as biomarkers in H. pylori-positive patients. Additionally, the study investigates the association between these markers and alterations in lipid profiles, as well as their involvement in the molecular mechanisms underlying gastric conditions like gastritis, particularly in the context of H. pylori infection. Materials and Methods: This study was conducted at Istanbul Avcılar Murat Kölük State Hospital’s General Surgery Outpatient Clinic. A total of 60 participants were included: 40 patients diagnosed with chronic gastritis (20 H. pylori-positive and 20 H. pylori-negative) and 20 healthy controls confirmed negative by 13C-urea breath test. Blood samples were collected for ELISA analysis of HIF-1α, HIF-2α, and P4H-TM levels. Additionally, lipid profiles were measured and compared among the groups. Results: No significant differences were found among the groups in terms of demographic factors such as age, sex, or body mass index (BMI). However, significant variations were observed in the levels of HIF-1α, HIF-2α, and P4H-TM across all groups (p < 0.001 for each marker). These markers were substantially elevated in the H. pylori-positive gastritis group compared to both the H. pylori-negative and healthy control groups. Receiver Operating Characteristic (ROC) curve analysis revealed that all evaluated markers exhibited strong diagnostic accuracy in differentiating H. pylori-positive individuals from other groups. HIF-1α (AUC: 0.983) and HIF-2α (AUC: 0.981) both achieved 100% sensitivity with specificities of 93.3% and 91.1%, respectively. P4H-TM showed an AUC of 0.927, with 85% sensitivity and 95.6% specificity. Conclusions: These findings indicate that HIF-1α, HIF-2α, and P4H-TM may serve as effective biomarkers for diagnosing H. pylori-positive patients and may be linked to changes in lipid metabolism. The elevated expression of these markers in response to H. pylori infection highlights their potential roles in the inflammatory and hypoxic pathways that contribute to the pathogenesis of gastric diseases such as gastritis.

UVB radiation impairs CD4+ and IFNγ+ cell responses, promoting IL-10+ cells and exacerbating lesions caused by Leishmania mexicana using a mouse model 30 days post-infection.

UVB radiation impairs CD4+ and IFNγ+ cell responses, promoting IL-10+ cells and exacerbating lesions caused by Leishmania mexicana using a mouse model 30 days post-infection.

Targeting the IL-6-Th17-Neutrophil Axis Reduces Local Inflammation in Stomatitis.

Recurrent aphthous stomatitis (RAS) is a common chronic oral disease with unclear pathogenesis. Chronic inflammation associated with RAS has been linked to the dysregulation of local immune responses. We used a murine model of acetic acid-induced chemical stomatitis (CS) to assess changes in the systemic and local immune environments of CS mice relative to healthy mice. Flow cytometry revealed a significant increase in neutrophil infiltration and elevated proportions of Th1 (CD4+IFN-γ+) and Th17 (CD4+IL-17a+) cells in the lingual mucosa of CS mice 7 d after CS induction, indicating an active inflammatory response in the CS immune microenvironment. Given that Th17 cells indirectly recruit neutrophils, we used Rorc-/- mice to evaluate the effects of Th17 cell depletion. Neutrophil infiltration was markedly reduced, and decreased tissue damage was observed in the lingual mucosa of Rorc-/- mice, as confirmed by hematoxylin and eosin staining. To further investigate the mechanism underlying Th17 cell generation in stomatitis, we induced CS in Il6ra-/- mice, which exhibited significantly reduced inflammatory cell infiltration and ulcer severity in the lingual mucosa. Treatment with an anti-Ly6G antibody treatment, which can directly target and deplete neutrophils, also significantly reduced local inflammation in the CS mouse immune microenvironment and diminished Th1 and Th17 cell infiltration, indicating a positive feedback loop between Th17 cells and neutrophils in stomatitis. In conclusion, the IL-6-Th17-neutrophil axis plays a critical role in stomatitis pathogenesis, suggesting that targeting this axis could present a novel immunotherapeutic strategy for alleviating mucosal damage in patients with RAS.

Tufted Hair Folliculitis Decalvans as a Clinical Diagnostic Sign

Folliculitis decalvans is a rare condition classified under neutrophilic primary scarring alopecias. Its etiopathogenesis has been linked to scalp colonization, mainly by Staphylococcus aureus, and to disruptions in the host's local immune response. Multiple treatment options exist, but none are specific or entirely effective. Oral antistaphylococcal antibiotics are commonly used, though recurrences are frequent. This is a chronic and progressive disease that leads to irreversible sequelae, which underscores the importance of early clinical diagnosis, with tufted hairs being a key diagnostic sign. This case is reported due to its unusual presentation in terms of patient age and sex.

Deciphering the Role of Biomaterial Surface Chemistry in Toll-Like Receptor-Mediated Immune Modulation.

The inflammatory response to biomaterials plays a critical role in determining the implant performance and longevity. As key early responders, macrophages detect the implant surface and orchestrate immune reactions. Biomaterial surface properties are a key modifiable factor that significantly influences macrophage activation and local immune response. Because macrophages depend on Toll-like receptor (TLR) signaling to identify and respond to foreign materials, understanding how biomaterials influence this pathway is crucial. In this study, we aim to investigate the role of surface chemistry in TLR signaling. To achieve this, we utilized plasma polymerization to engineer biomaterial surfaces with four distinct surface chemistries. Synchrotron ATR-FTIR microspectroscopy revealed shifts in the infrared spectra, indicating changes in macromolecules in macrophages upon interaction with various surface coatings. Gene expression analysis showed that macrophages cultured on hydrocarbon-rich surfaces exhibited increased TLR2 expression and upregulated proinflammatory genes, including TNF-α, IL-1β, IL-6, and iNOS. In contrast, surfaces rich in carboxylic acid, amine, and oxazoline functionalities heightened TLR4 expression and upregulated anti-inflammatory genes, such as IL-1RA, arginase, and IL-10. These findings highlight the impact of biomaterial surface chemistry on immune signaling pathways, demonstrating that surface modifications can actively influence the polarization of macrophages. By leveraging these insights, we can refine biomaterial design to create immune-modulatory surfaces that optimize healing, reduce inflammation, and enhance success with implantable medical devices.

Coordinated early immune response in the lungs is required for effective control of SARS-CoV-2 replication

Despite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P.1 vaccines and WA-1 or P.1 infection are immunized with a bivalent WA-1/Omicron BA.5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA.5-specific responses. Reinfection with heterologous Omicron XBB.1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-naïve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69+CD103+ lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.

Characterization of B Cell Responses in Rainbow Trout (Oncorhynchus Mykiss) Affected by Red Mark Syndrome.

Red mark syndrome (RMS) is a disease affecting rainbow trout. Although the precise etiology of this disease is still under debate, a Midichloria-like organism (MLO) is suspected as the triggering agent. RMS provokes characteristic skin lesions. Previous investigations pointed to a local immune response characterized by a B cell influx. To elaborate on these findings, here, this study extensively characterizes systemic and local B cell responses in RMS-affected fish. The local influx of IgM+ B cells to the skin lesions is confirmed, and a differentiation of these B cells to plasma-like cells is demonstrated. IgM repertoires suggested a polyclonal activation of local B cells and some trafficking between skin and head kidney. Finally, the fact that transcripts of the gene coding for MLO 16S rRNA are found in sorted skin IgM+ B cells and non-IgM+ skin leukocytes reveals the capacity of this intracellular bacterium to be internalized by B cells, where it may possibly directly interfere with intracellular pathways. The data significantly advances the knowledge on RMS and provides another example of a fish pathology in which fish B cells seem pivotal, possibly because of the specific ways in which teleost B cells intrinsically sense and respond to pathogens.

Age-Related Impairment of Innate and Adaptive Immune Responses Exacerbates Herpes Simplex Viral Infection

Immune function declines with age, leading to increased vulnerability of the elderly to viral infectious pathogens. The mechanisms by which aging negatively impacts the innate and adaptive immune system, leading to enhanced susceptibility to respiratory viral pathogens, remain incompletely understood. In the present study, we utilized a mouse model of infection with herpes simplex virus type 1 (HSV-1), a virus that can infect the lungs and lead to pneumonia, a rare but serious health concern in the elderly. Following intranasal inoculation of young (6 weeks), adult (36 weeks), and aged mice (68 weeks) with HSV-1 (KOS strain) we: (i) compared the local and systemic immune responses to infection in young, adult, and aged mice, and (ii) correlated the level and type of immune responses to protection against HSV-1 infection and disease. Compared to young and adult mice, aged mice displayed: (i) increased activation of epithelial cells with a decreased expression of TLR3; (ii) increased activation of dendritic cells with increased expression of MHC-I, MHC-II, and CD80/86; (iii) decreased production of type-I interferons; (iv) delayed production of anti-inflammatory cytokines and chemokines in the lungs; and (v) impairment frequencies of functional HSV-specific CD107+IFN-γ+CD8+ T cells associated with the increased incidence of viral infection and disease. These findings suggest that age-related impairments in innate and adaptive immune responses may exacerbate respiratory viral infections and disease in the elderly.

Influence of Paratuberculosis Vaccination on the Local Immune Response in Experimentally Infected Calves: An Immunohistochemical Analysis

Vaccination remains the most cost-effective way to control clinical paratuberculosis in dairy herds, but its effect on the immune response at the intestine have been poorly characterized. The aim of this study was to evaluate the expression of toll-like receptor (TLR)-1, TLR2, TLR4, TLR9, interferon (IFN)-γ, inducible nitric oxide synthase (iNOS) and cluster of differentiation (CD)-204 in calves vaccinated with Silirum® and then experimentally infected with paratuberculosis, using immunohistochemical techniques. Samples of the injection-site granuloma, scapular lymph node, intestine and mesenteric lymph nodes were studied. Lesions were classified as focal, multifocal and diffuse paucibacillary (lymphocytic). The immunolabeling for TLR1, TLR2, TLR4 and IFN-γ was assessed according to the number of immunolabeled cells, while TLR9, iNOS and CD204 immunolabeling in the lesions was evaluated using a histological score (H-score). Vaccinated calves with focal forms showed a significant increase in the number of macrophages immunolabeled TLR2 at the intestine and in the H-score values for iNOS in the granulomas. A greater immunolabeling of TLR2 and IFN-γ was detected at the injection-site granuloma. Animals with multifocal lesions, regardless of the vaccination status, showed lower numbers of TLR2+ macrophages and higher H-score values for CD204 in the granulomas. Thus, the protection conferred by the Silirum® vaccine is associated with an enhanced immunological response in the intestine.

Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor: results from PNOC005.

Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. PNOC005 is a phase 1 clinical trial investigating the safety and tolerability of intratumoral or intrathecal administration of oncolytic measles virus (MV-NIS) in children and young adults with recurrent medulloblastoma (MB) or atypical teratoid/rhabdoid tumor (ATRT). We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model. MV-NIS given intratumorally or via repeat intrathecal dosing was safe.MV-NIS prolonged survival in murine models but did not demonstrate additive benefit with ICI. No changes in tumor-infiltrating immune-cell composition or activation were observed in response to MV-NIS treatment; however, MV-NIS induced local expression of neutralizing antibodies, complement cascade, and phagocytosis-related genes. This is the first trial investigating intratumoral as well as repeated intrathecal delivery of MV-NIS in children with MB and ATRT. We show that therapy is safe and well-tolerated with minimal adverse effects. Immune markers and biologic correlates preliminarily indicate anti-viral effects in tumors.

Intratumoral immunotherapy prior to cancer surgery, a promising therapeutic approach.

Cancer immunotherapy has made astonishing progress in the last 10-15 years, and the rate of progress is accelerating. However, only 20 to 40% of patients benefit from this therapy with most immunotherapy applied post discovery of metastatic disease when therapeutic impact is more difficult to achieve. The first line of treatment for many patients following diagnosis is surgery. Neoadjuvant immunotherapy, i.e. administration of immune therapy prior to surgery, has the potential to improve overall survival rates. Many patients without detectable metastases are diagnosed with a high risk of future metastasis and could benefit from effective neoadjuvant immunotherapy. An ideal neoadjuvant immune therapy will stimulate immune response against the identified tumor as well as undetected metastasis and be safe with minimal adverse events. In addition, the antitumor immune response it generates should not be blocked by subsequent surgery and should not delay the normal timeline of surgery. Finally, it should be relatively inexpensive. These features describe intratumoral immunotherapy (ITIT), a therapeutic approach that directly administers immune stimulatory agents or treatments into the tumor. By delivering the therapy directly into the tumor, it enhances local drug concentration while minimizing nonspecific immune activation and adverse events associated with systemic immunotherapy. ITIT can generate effective local immune response against tumor antigens, which expands the pool of tumor-recognizing effector T cells. ITIT induces and activates tumor specific T cell within days after the treatment, so surgery is not delayed. Tumor-recognizing effector T cells generated locally attack cancer both locally and systemically, targeting metastasis through the "abscopal effect". Neoadjuvant ITIT options are extensive and expanding and need research into optimal options to combine and associated dosing and timing. With the needed effort, neoadjuvant ITIT will develop into a safe, rapid and effective addition to current cancer therapies.

Abstract PS4-09: Spatial Omics Analysis Uncovers Microenvironmental Remodeling and Immune Dynamics in T-DXd Resistant Metastatic Breast Cancer

Abstract Trastuzumab deruxtecan (T-DXd) is the standard of care for HER2+ or HER2 low metastatic breast cancer (mBC). However, approximately 20% of patients exhibit resistance to T-DXd therapy. As the development of more antibody-drug conjugate (ADC) therapies progresses, understanding ADC resistance mechanisms is critical. Our study aims to elucidate the etiology of ADC resistance, such as characterizing molecular changes and identifying novel biomarkers in tumor-immune interactions between T-DXd responsive (R) and non-responsive (NR) patients with mBC. We employed Nanostring’s GeoMX spatial proteomics and transcriptomics profiling technology to analyze 29 metastatic tissue sections (15R, 14NR) from heavily pre-treated patients with HER2+/low mBC, prior to T-DXd treatment. For each section, 6-8 circular regions of interest (ROIs) with a diameter of 300µm were chosen by researchers blinded to T-DXd R vs. NR outcomes and HER2 scores. ROIs were selected to capture spatially diverse tumor-dense and tumor-sparse regions. Immune markers, stromal markers, and HER2 expression levels were quantified for each ROI. Consistent immune and stromal features related to T-DXd resistance were identified across various metastatic sites, including brain, bone, liver, lymph node, chest wall, and lung. NR tumors were characterized by relative immunosuppression and a disorganized immune response, with consistent upregulation of fibronectin and, surprisingly, granzyme B. Local immune response significantly varied based on HER2 expression. Organ-specific characteristics were also observed: Bone metastases showed an increased correlation between various immune markers and fibronectin in NR, suggesting that fibronectin may modulate immune infiltration and promote a supportive microenvironment for tumor growth. In contrast, chest wall metastases showed loss of correlation between various immune markers and smooth muscle actin in NR. This suggests that a remodeled, less dense smooth muscle environment might reduce physical barriers, potentially allowing better immune cell infiltration and activity in responsive tumors. Furthermore, a subset of these patient samples was selected for spatial whole transcriptomic analysis to gain deeper insights. Citation Format: Glori Das, Matthew Vasquez, Jeffrey Zhang, Ji-Hoon Lee, Yuan Gao, Jilun Zhang, Jenny Chang, Xiaoxian Li, Hong Zhao, Stephen T.C. Wong. Spatial Omics Analysis Uncovers Microenvironmental Remodeling and Immune Dynamics in T-DXd Resistant Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS4-09.

Tissue-specific transcriptomic adaptation in three strains of chickens during coinfections with parasites

BackgroundThe widespread adoption of non-caged production systems contributes to the pathogenesis of coinfections with gastrointestinal nematodes and Histomonas meleagridis, triggering local and systemic immune and metabolic responses in chickens. This study investigated transcriptomic adaptation of tissues two weeks after experimental coinfections with Ascaridia galli, Heterakis gallinarum, and H. meleagridis in Lohmann Brown (LB), Lohmann Dual (LD), and Ross-308 (R) male chickens, which differ in growth rates (R > LD > LB).ResultsRNA sequencing of the jejunum, caecum, and liver tissues revealed tissue-specific, strain-dependent transcriptional responses. Coinfection was confirmed during necropsy, and Ascaris-specific antibodies as well as alpha-1-acid glycoprotein were significantly higher in infected birds (p < 0.01). The caecum exhibited the highest unique differentially expressed genes, DEGs (n = 4,094), corresponding to significant activation of complex immune pathways and inhibition of metabolic pathways (p < 0.01). Jejunum DEGs (n = 760) primarily related to muscle contraction, collagen metabolism notably in LB and LD strains. The liver displayed fewer unique DEGs (n = 266) but prominently activated immune responses, especially in R chickens.ConclusionIn general, slower-performing strains effectively initiated responses favouring worm expulsion and tissue repair in the jejunum, whereas high-performing strains predominantly showed inflammatory responses in the caecum and liver. These findings highlight tissue-specific adaptations underlying strain-dependent tolerance to coinfections with mixed parasites.

Harnessing the immune system and developing targeted vaccines: Overall strategies of leveraging the body’s natural defense mechanisms to enhance cancer treatment

The immune system serves as a pivotal defense mechanism against foreign materials and abnormal cells, including cancer. Cancer immunotherapy exploits the immune system’s potential to target and eliminate malignant tumor cells, either through immunization or therapeutic antibodies. The presence of unusual antigens, such as GD2 and ErbB2, provides specific targets for immunotherapy. Next-generation immunotherapy, combining antibodies with immune-stimulatory cytokines, presents a promising avenue to enhance localized immune responses against tumors while minimizing systemic side effects. Challenges in cancer vaccine development include the diversity of tumor cells and their similarity to normal cells. Recent decades have seen significant progress in cancer vaccine development, with US Food and Drug Administration-approved therapeutic vaccines like Sipuleucel-T for prostate cancer and BCG for bladder cancer. However, challenges related to reproducibility and efficacy in cancer subjects persist. The current landscape of cancer treatment is undergoing a transformative shift, with combination therapies incorporating cytokines, tumor-associated antigens, and monoclonal antibodies becoming integral to treatment strategies. This dynamic approach reflects ongoing efforts to overcome challenges in developing effective therapeutic cancer vaccines and underscores the commitment to advancing the field. Advances in genomics allow for the development of personalized cancer vaccines tailored to an individual’s unique tumor profile, addressing the challenge of intratumoral heterogeneity. Combining cancer vaccines with other immunotherapies, such as immune checkpoint inhibitors, may enhance the overall anti-cancer immune response. Identifying and targeting neoantigens (mutated proteins specific to cancer cells) offers a more precise and selective approach to cancer vaccine development. These evolving strategies emphasize leveraging the body’s natural defense mechanisms to enhance the overall efficacy of cancer treatment, marking a departure from traditional approaches like surgery, chemotherapy, and radiation.