InVivoMAb polyclonal Armenian hamster IgG
Product Details
The polyclonal Armenian hamster IgG is purified from Armenian hamster serum. It is ideal for use as a non-reactive control IgG for Armenian hamster antibodies in most in vivo and in vitro applications.Specifications
| Isotype | Armenian hamster IgG |
|---|---|
| Recommended Dilution Buffer | InVivoPure pH 7.0 Dilution Buffer |
| Conjugation | This product is unconjugated. Conjugation is available via our Antibody Conjugation Services. |
| Formulation |
PBS, pH 7.0 Contains no stabilizers or preservatives |
| Endotoxin |
<2EU/mg (<0.002EU/Ī¼g) Determined by LAL gel clotting assay |
| Purity |
>95% Determined by SDS-PAGE |
| Sterility | 0.2 Āµm filtration |
| Production | Purified from Armenian hamster serum |
| Purification | Protein G |
| RRID | AB_1107773 |
| Molecular Weight | 150 kDa |
| Murine Pathogen Tests |
Ectromelia/Mousepox Virus: Negative Hantavirus: Negative K Virus: Negative Lactate Dehydrogenase-Elevating Virus: Negative Lymphocytic Choriomeningitis virus: Negative Mouse Adenovirus: Negative Mouse Cytomegalovirus: Negative Mouse Hepatitis Virus: Negative Mouse Minute Virus: Negative Mouse Norovirus: Negative Mouse Parvovirus: Negative Mouse Rotavirus: Negative Mycoplasma Pulmonis: Negative Pneumonia Virus of Mice: Negative Polyoma Virus: Negative Reovirus Screen: Negative Sendai Virus: Negative Theilerās Murine Encephalomyelitis: Negative |
| Storage | The antibody solution should be stored at the stock concentration at 4Ā°C. Do not freeze. |
Additional Formats
Recommended Products
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Recommended Dilution Buffer
InVivoPure pH 7.0 Dilution Buffer
Ariyan, C. E., et al. (2018). "Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade" Cancer Immunol Res 6(2): 189-200. PubMed
Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8(+) and CD4(+) T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy.
Li, C., et al. (2015). "ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy" EMBO Mol Med 7(6): 754-769. PubMed
PD-1 negatively regulates CD8(+) cytotoxic T lymphocytes (CTL) cytotoxicity and anti-tumor immunity. However, it is not fully understood how PD-1 expression on CD8(+) CTL is regulated during anti-tumor immunotherapy. In this study, we have identified that the ADAP-SKAP55 signaling module reduced CD8(+) CTL cytotoxicity and enhanced PD-1 expression in a Fyn-, Ca(2+)-, and NFATc1-dependent manner. In DC vaccine-based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD-1 expression in CD8(+) effector cells. Interestingly, CTLA-4 levels and the percentages of tumor infiltrating CD4(+)Foxp3(+) Tregs remained unchanged. Furthermore, adoptive transfer of SKAP55-deficient or ADAP-deficient CD8(+) CTLs significantly blocked tumor growth and increased anti-tumor immunity. Pretreatment of wild-type CD8(+) CTLs with the NFATc1 inhibitor CsA could also downregulate PD-1 expression and enhance anti-tumor therapeutic efficacy. Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy.
Imai, Y., et al. (2015). "Cutting Edge: PD-1 Regulates Imiquimod-Induced Psoriasiform Dermatitis through Inhibition of IL-17A Expression by Innate gammadelta-Low T Cells" J Immunol 195(2): 421-425. PubMed
Programmed cell death 1 (PD-1) is a key regulatory molecule that has been targeted in human cancers, including melanoma. In clinical testing, Abs against PD-1 have resulted in psoriasiform dermatitis (PsD). To determine whether PD-1 regulates PsD, we compared skin responses of PD-1-deficient (PD-1KO) mice and wild-type (WT) controls in an imiquimod (IMQ)-induced murine model of psoriasis. PD-1KO mice showed severe epidermal hyperplasia, greater neutrophilic infiltration, and higher expression of Th17 cytokines (versus WT mice). IMQ exposure increased PD-1 expression by skin gammadelta-low (GDL) T cells and enhanced expression of PD-L1 by keratinocytes. Three-fold increases in the percentage of IL-17A(+) GDL T cells were observed in skin cell suspensions derived from IMQ-treated PD-1KO mice (versus WT controls), suggesting that the lack of PD-1 has a functional effect not only on alphabeta T cells, but also on GDL T cells, and that PD-1 may play a regulatory role in PsD.
Awe, O., et al. (2015). "PU.1 Expression in T Follicular Helper Cells Limits CD40L-Dependent Germinal Center B Cell Development" J Immunol . PubMed
PU.1 is an ETS family transcription factor that is important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development and in limiting Th2 cytokine production. Whether PU.1 has functions in other Th lineages is not clear. In this study, we examined the effects of ectopic expression of PU.1 in CD4+ T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1lck-/-) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1lck-/- mice had increased numbers of Tfh cells, increased germinal center B cells (GCB cells), and increased Ab production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1lck-/- mice compared with control mice. Finally, although blockade of IL-21 did not affect GCB cells in Sfpi1lck-/- mice, anti-CD40L treatment of immunized Sfpi1lck-/- mice decreased GCB cell numbers and Ag-specific Ig concentrations. Together, these data indicate an inhibitory role for PU.1 in the function of Tfh cells, germinal centers, and Tfh-dependent humoral immunity.
Ozdemir, B. C., et al. (2014). "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival" Cancer Cell 25(6): 719-734. PubMed
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete alphaSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
Ballesteros-Tato, A., et al. (2014). "Epitope-specific regulation of memory programming by differential duration of antigen presentation to influenza-specific CD8(+) T cells" Immunity 41(1): 127-140. PubMed
Memory CD8(+) T cells are programmed during the primary response for robust secondary responsiveness. Here we show that CD8(+) T cells responding to different epitopes of influenza virus received qualitatively different signals during the primary response that altered their secondary responsiveness. Nucleoprotein (NP)-specific CD8(+) T cells encountered antigen on CD40-licensed, CD70-expressing, CD103(-)CD11b(hi) dendritic cells (DCs) at later times in the primary response. As a consequence, they maintained CD25 expression and responded to interleukin-2 (IL-2) and CD27, which together programmed their robust secondary proliferative capacity and interferon-gamma (IFN-gamma)-producing ability. In contrast, polymerase (PA)-specific CD8(+) T cells did not encounter antigen-bearing, CD40-activated DCs at later times in the primary response, did not receive CD27 and CD25 signals, and were not programmed to become memory CD8(+) T cells with strong proliferative and cytokine-producing ability. As a result, CD8(+) T cells responding to abundant antigens, like NP, dominated the secondary response.
Van der Jeught, K., et al. (2014). "Intratumoral administration of mRNA encoding a fusokine consisting of IFN-beta and the ectodomain of the TGF-beta receptor II potentiates antitumor immunity" Oncotarget 5(20): 10100-10113. PubMed
It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8(+) cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-beta and the ectodomain of the transforming growth factor-beta receptor II, referred to as Fbeta(2), showed therapeutic potential. The treatment efficacy was dependent on CD8(+) T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fbeta(2) to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fbeta(2) enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fbeta(2), can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.
Khmaladze, I., et al. (2014). "Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice" Proc Natl Acad Sci U S A 111(35): E3669-3678. PubMed
Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gammadelta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcgamma receptor III, mast cells, and histamine) and adaptive immune players (alphabeta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gammadelta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
Gopinath, S., et al. (2014). "Role of disease-associated tolerance in infectious superspreaders" Proc Natl Acad Sci U S A 111(44): 15780-15785. PubMed
Natural populations show striking heterogeneity in their ability to transmit disease. For example, a minority of infected individuals known as superspreaders carries out the majority of pathogen transmission events. In a mouse model of Salmonella infection, a subset of infected hosts becomes superspreaders, shedding high levels of bacteria (>10(8) cfu per g of feces) but remain asymptomatic with a dampened systemic immune state. Here we show that superspreader hosts remain asymptomatic when they are treated with oral antibiotics. In contrast, nonsuperspreader Salmonella-infected hosts that are treated with oral antibiotics rapidly shed superspreader levels of the pathogen but display signs of morbidity. This morbidity is linked to an increase in inflammatory myeloid cells in the spleen followed by increased production of acute-phase proteins and proinflammatory cytokines. The degree of colonic inflammation is similar in antibiotic-treated superspreader and nonsuperspreader hosts, indicating that the superspreader hosts are tolerant of antibiotic-mediated perturbations in the intestinal tract. Importantly, neutralization of acute-phase proinflammatory cytokines in antibiotic-induced superspreaders suppresses the expansion of inflammatory myeloid cells and reduces morbidity. We describe a unique disease-associated tolerance to oral antibiotics in superspreaders that facilitates continued transmission of the pathogen.
Church, S. E., et al. (2014). "Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells" Eur J Immunol 44(1): 69-79. PubMed
Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4(+) T cells enhance CD8(+) T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4(+) transgenic T cells-CD4(+) T cells and pmel-CD8(+) T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p = 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8(+) T cells with tumor-specific cytokine expression. When combined with CD4(+) T cells, transfer of total (naive and effector) or effector CD8(+) T cells were highly effective, suggesting CD4(+) T cells can help mediate therapeutic effects by maintaining function of activated CD8(+) T cells. In addition, CD4(+) T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8(+) T cells recovered from mice treated with both CD8(+) and CD4(+) T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4(+) T cells help reduce CD8(+) T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4(+) and CD8(+) T cells for treatment of patients with cancer.
Youlin, K., et al. (2012). "Combination immunotherapy with 4-1BBL and CTLA-4 blockade for the treatment of prostate cancer" Clin Dev Immunol 2012: 439235. PubMed
Immune regulation has been shown to be involved in the progressive growth of some murine tumours. Interruption of immune regulatory pathways via activation of 4-1BB or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade appears to be a promising strategy for cancer immunotherapy. In this study, we examined the effectiveness of 4-1BBL-expressing tumor cell vaccine in combination with CTLA-4 blockade on rejection of murine prostate cancer RM-1. We found that the combination of both a vaccine consisting of 4-1BBL-expressing RM-1 cells and CTLA-4 blockade resulted in regression of RM-1 tumors and a significant increase in survival of the tumour cell recipients, compared to that of either treatment alone. The combined vaccination resulted in higher CTL against RM-1 cells and increased secretion of IFN-gamma, TNF-alpha, and IL-2 in the mix-cultured supernatant. These results suggest that combining activation of 4-1BB and blockade of CTLA-4 may offer a new strategy for prostate cancer immunotherapy.
Bortnick, A., et al. (2012). "Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens" J Immunol 188(11): 5389-5396. PubMed
The signals required to generate long-lived plasma cells remain unresolved. One widely cited model posits that long-lived plasma cells derive from germinal centers (GCs) in response to T cell-dependent (TD) Ags. Thus, T cell-independent (TI) Ags, which fail to sustain GCs, are considered ineffective at generating long-lived plasma cells. However, we show that long-lived hapten-specific plasma cells are readily induced without formation of GCs. Long-lived plasma cells developed in T cell-deficient mice after a single immunization with haptenated LPS, a widely used TI Ag. Long-lived plasma cells also formed in response to TD Ag when the GC response was experimentally prevented. These observations establish that long-lived plasma cells are induced in both TI and TD responses, and can arise independently of B cell maturation in GCs.
Waitz, R., et al. (2012). "Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy" Cancer Res 72(2): 430-439. PubMed
Thermal ablation to destroy tumor tissue may help activate tumor-specific T cells by elevating the presentation of tumor antigens to the immune system. However, the antitumor activity of these T cells may be restrained by their expression of the inhibitory T-cell coreceptor CTLA-4, the target of the recently U.S. Food and Drug Administration-approved antibody drug ipilumimab. By relieving this restraint, CTLA-4-blocking antibodies such as ipilumimab can promote tumor rejection, but the full scope of their most suitable applications has yet to be fully determined. In this study, we offer a preclinical proof-of-concept in the TRAMP C2 mouse model of prostate cancer that CTLA-4 blockade cooperates with cryoablation of a primary tumor to prevent the outgrowth of secondary tumors seeded by challenge at a distant site. Although growth of secondary tumors was unaffected by cryoablation alone, the combination treatment was sufficient to slow growth or trigger rejection. In addition, secondary tumors were highly infiltrated by CD4(+) T cells and CD8(+) T cells, and there was a significant increase in the ratio of intratumoral T effector cells to CD4(+)FoxP3(+) T regulatory cells, compared with monotherapy. These findings documented for the first time an effect of this immunotherapeutic intervention on the intratumoral accumulation and systemic expansion of CD8(+) T cells specific for the TRAMP C2-specific antigen SPAS-1. Although cryoablation is currently used to treat a targeted tumor nodule, our results suggest that combination therapy with CTLA-4 blockade will augment antitumor immunity and rejection of tumor metastases in this setting.
Coley, S. M., et al. (2009). "IFN-gamma dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses" J Immunol 182(1): 225-233. PubMed
CD8 T cells are necessary for costimulation blockade-resistant rejection. However, the mechanism by which CD8 T cells mediate rejection in the absence of major costimulatory signals is poorly understood. IFN-gamma promotes CD8 T cell-mediated immune responses, but IFN-gamma-deficient mice show early graft loss despite costimulation blockade. In contrast, we found that IFN-gamma receptor knockout mice show dramatically prolonged graft survival under costimulation blockade. To investigate this paradox, we addressed the effects of IFN-gamma on T cell alloresponses in vivo independent of the effects of IFN-gamma on graft survival. We identified a donor-specific CD8 T cell breakthrough response temporally correlated with costimulation blockade-resistant rejection. Neither IFN-gamma receptor knockout recipients nor IFN-gamma-deficient recipients showed a CD8 breakthrough response. Graft death on IFN-gamma-deficient recipients despite costimulation blockade could be explained by the lack of IFN-gamma available to act on the graft. Indeed, the presence of IFN-gamma was necessary for graft survival on IFN-gamma receptor knockout recipients, as either IFN-gamma neutralization or the lack of the IFN-gamma receptor on the graft precipitated early graft loss. Thus, IFN-gamma is required both for the recipient to mount a donor-specific CD8 T cell response under costimulation blockade as well as for the graft to survive after allotransplantation.
- Cell Biology,
- Immunology and Microbiology
Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
In Nature Communications on 20 May 2025 by VanPortfliet, J. J., Lei, Y., et al.
Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD. Ā© 2025. The Author(s).
- Cancer Research
Interferon-Ī³ orchestrates leptomeningeal anti-tumour response.
In Nature on 14 May 2025 by RemÅ”Ćk, J., Tong, X., et al.
Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNĪ³ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lungĀ cancer, breast cancerĀ and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNĪ³ or its receptor fail to controlĀ the growth of leptomeningealĀ metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNĪ³ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNĪ³ signalling and suggests an immune-therapeutic approach against tumours within this space. Ā© 2025. The Author(s).
- Cancer Research,
- Immunology and Microbiology
BTG2-deficient mast cells remodel the tumor and tumor-draining lymph node microenvironment leading to chemotherapy resistance in breast cancer.
In Frontiers in Immunology on 2 May 2025 by Zhang, X., Wang, J., et al.
Breast cancer is currently the most frequently diagnosed malignancy worldwide, with chemotherapy resistance being a major contributor to breast cancer-related mortality and distant metastasis. The role of lymph nodes as the initial site of immune defense remains controversial, particularly regarding whether complete dissection or preservation is necessary during breast cancer surgery. We performed single-cell RNA sequencing (scRNA-seq) on cells derived from metastatic tumor draining lymph nodes and tumor tissue of four breast cancer patients exhibiting either sensitivity or resistance to neoadjuvant chemotherapy (NAC). Mast cells with low BTG2 expression were identified in the metastatic lymph nodes and in situ tumor of the NAC-resistant group. Mast cells with low BTG2 expression have enhanced migratory capacity and are preferentially recruited to lymph nodes by cytokines such as CCL5, secreted by tumor cells during metastasis. Mechanistically, the mast cells with low BTG2 suppress anti-tumor immunity by inducing Treg cell production through IL-2 secretion, particularly within tumor-draining lymph nodes. Furthermore, the mast cells with low BTG2 promote NAC resistance by inducing fibroblast precursor cells to differentiate into Ī±-SMA-positive fibroblasts via the Tryptase-PAR-2-pERK signaling pathway, leading to excessive collagen fiber production. Finally, we demonstrated that combining radiotherapy upregulating the expression of BTG2 in mast cells with chemotherapy enhances therapeutic efficacy in a murine model. This study highlights the immunoregulatory role of mast cells in the breast cancer tumor microenvironment and establishes a link between BTG2 expression in mast cells and neoadjuvant chemotherapy response. These findings provide a foundational basis for preserving functional lymph nodes and optimizing combined radiotherapy treatment strategies. Copyright Ā© 2025 Zhang, Wang, Liu, Wen, Kang, Fang and Ren.
- In Vivo,
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
Single-cell transcriptomic analysis reveals gut microbiota-immunotherapy synergy through modulating tumor microenvironment.
In Signal Transduction and Targeted Therapy on 2 May 2025 by Cao, M., Deng, Y., et al.
The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor (ICI) based immunotherapy, but the underlying mechanisms remain unclear at the single-cell resolution. Using single-cell RNA sequencing and subsequent validations, we investigate gut microbiota-ICI synergy by profiling the tumor microenvironment (TME) and elucidating critical cellular interactions in mouse models. Our findings reveal that intact gut microbiota combined with ICIs may synergistically increase the proportions of CD8+, CD4+, and Ī³Ī“ T cells, reduce glycolysis metabolism, and reverse exhausted CD8+ T cells into memory/effector CD8+ T cells, enhancing antitumor response. This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1+ tumor-associated macrophages (TAMs) to Cd74+ TAMs, which act as antigen-presenting cells (APCs). These macrophage subtypes show a negative correlation within tumors, particularly during fecal microbiota transplantation. Depleting Spp1+ TAMs in Spp1 conditional knockout mice boosts ICI efficacy and T cell infiltration, regardless of gut microbiota status, suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1+ TAMs during macrophage reprogramming on immunotherapy outcomes. Mechanistically, we propose a Ī³Ī“ T cell-APC-CD8+ T cell axis, where gut microbiota and ICIs enhance Cd40lg expression on Ī³Ī“ T cells, activating Cd40 overexpressing APCs (e.g., Cd74+ TAMs) through CD40-CD40L-related NF-ĪŗB signaling and boosting CD8+ T cell responses via CD86-CD28 interactions. These findings highlight the potential importance of Ī³Ī“ T cells and SPP1-related macrophage reprogramming in activating CD8+ T cells, as well as the synergistic effect of gut microbiota and ICIs in immunotherapy through modulating the TME. Ā© 2025. The Author(s).
- In Vivo,
- Mus musculus (House mouse),
- Cancer Research
Resistance to anti-LAG-3 plus anti-PD-1 therapy in head and neck cancer is mediated by Sox9+ tumor cells interaction with Fpr1+ neutrophils.
In Nature Communications on 28 April 2025 by Wang, X., Cheng, M., et al.
Relatlimab and nivolumab combination therapy shows significant efficacy in treating various types of cancer. Current research on the molecular mechanisms of this treatment is abundant, but in-depth investigations into post-treatment resistance remain notably lacking. In this study, we identify significant enrichment of SRY (sex determining region Y)-box 9 (Sox9)+ tumor cells in resistant samples using single cell RNA sequencing (scRNAseq) in a head and neck squamous cell carcinoma (HNSCC) mouse model. In addition, Sox9 directly regulates the expression of annexin A1 (Anxa1), mediating apoptosis of formyl peptide receptor 1 (Fpr1)+ neutrophils through the Anxa1-Fpr1 axis, which promotes mitochondrial fission, inhibits mitophagy by downregulating BCL2/adenovirus E1B interacting protein 3 (Bnip3) expression and ultimately prevents the accumulation of neutrophils in tumor tissues. The reduction of Fpr1+ neutrophils impairs the infiltration and tumor cell-killing ability of cytotoxic Cd8 T and Ī³Ī“T cells within the tumor microenvironment, thereby leading to the development of resistance to the combination therapy. We further validate these findings using various transgenic mouse models. Overall, this study comprehensively explains the mechanisms underlying resistance to the anti-LAG-3 plus anti-PD-1 combination therapy and identifies potential therapeutic targets to overcome this resistance. Ā© 2025. The Author(s).
- Cancer Research,
- Immunology and Microbiology
Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis
Preprint on BioRxiv : the Preprint Server for Biology on 26 April 2025 by Ngwa, V. M., Hwang, Y., et al.
Targeted therapies have improved survival for lung adenocarcinoma patients. However, similar advances are lacking for lung squamous carcinoma (LUSC). Advances in immunotherapy have shown some promise, but the overall response rate remains low in LUSC. Here, we demonstrate that the mTORC2 signaling pathway represents an actionable target in LUSC to improve anti-tumor immune responses. We show that genetic alterations affecting the mTORC2 pathway are common among patients with LUSC tumors, and targeting mTORC2 reduces LUSC tumor growth in mouse models. Transcriptomics reveal that mTORC2-deficient LUSC cells exhibit reduced expression of glycolytic and hypoxia-related genes. In agreement, loss of mTORC2 signaling decreases lactate levels in tumor-interstitial fluid, creating reduced acidity within the tumor microenvironment. Interestingly, mTORC2-deficient LUSC cells also exhibited reduced expression of the pH-sensitive VISTA ligand PSGL-1 in a HIF-2Ī± dependent mechanism. LUSC patients, but not those with LUAD, display a positive correlation in expression between HIF-2Ī± and PSGL-1, suggesting a distinct association among mTORC2, HIF-2Ī±, and immune responses in LUSC. Indeed, mTORC2 loss-of-function enhanced CD8 + T cell activation in tumors, while use of anti-VISTA immunotherapy reduced LUSC tumor burden only in the presence of intact mTORC2 signaling. Collectively, these data describe an important role of mTORC2 signaling in LUSC tumors and demonstrate the therapeutic potential of targeting the mTORC2/PSGL-1/VISTA axis in patients that are non-responsive to current therapies.
- Cancer Research,
- Immunology and Microbiology
ULBP2 Promotes Tumor Progression by Suppressing NKG2D-Mediated Anti-Tumor Immunity.
In International Journal of Molecular Sciences on 24 March 2025 by Yamane, K., Yamaguchi, K., et al.
UL-16 binding protein 2 (ULBP2), a human NKG2D ligand, has been identified as a poor prognostic factor in several cancers based on recent comprehensive analyses of immune-related genes using the Cancer Genome Atlas datasets. Despite its clinical significance, the functional role of ULBP2 in vivo remains largely unknown. In this study, we investigated the role of ULBP2 in modulating anti-tumor immunity using murine melanoma cell lines engineered to stably express surface-expressed or soluble ULBP2. Subcutaneous transplantation of ULBP2-expressing melanoma cells into syngeneic mice resulted in accelerated tumor growth, mediated by surface-expressed ULBP2, through the suppression of NKG2D-dependent immune responses. In vitro experiments revealed that sustained exposure to tumor-expressed ULBP2 reduced NKG2D expression and cytotoxic activity of splenocytes. In contrast, soluble ULBP2 did not significantly affect tumor growth or immune responses. These findings suggest that surface-expressed ULBP2 plays a pivotal role in tumor immune evasion and highlight its potential as a therapeutic target to enhance anti-tumor immunity.
- Cancer Research
Inhibitors of oncogenic Kras specifically prime CTLA4 blockade to transcriptionally reprogram Tregs and overcome resistance to suppress pancreas cancer
Preprint on BioRxiv : the Preprint Server for Biology on 4 March 2025 by Mahadevan, K. K., Maldonado, A. S., et al.
Lack of sustained response to oncogenic Kras (Kras*) inhibition in preclinical models and patients with pancreatic ductal adenocarcinoma (PDAC) emphasizes the need to identify impactful synergistic combination therapies to achieve robust clinical benefit. Kras* targeting results in an influx of global T cell infiltrates including Tregs, effector CD8 + T cells and exhausted CD8 + T cells expressing several immune checkpoint molecules in PDAC. Here, we probe whether the T cell influx induced by diverse Kras* inhibitors open a therapeutic window to target the adaptive immune response in PDAC. We show a specific synergy of anti-CTLA4 immune checkpoint blockade with Kras* targeting primed by Kras G12D allele specific inhibitor, MRTX1133 and multi-selective pan-RAS inhibitor, RMC-6236, both currently in clinical testing phase. In contrast, attempted therapeutic combination following Kras* targeting with multiple checkpoint inhibitors, including anti-PD1, anti-Tim3, anti-Lag3, anti-Vista and anti-4-1BB agonist antibody failed due to compensatory mechanisms mediated by other checkpoints on exhausted CD8 + T cells. Anti-CTLA4 therapy in Kras* targeted PDAC transcriptionally reprograms effector T regs to a naĆÆve phenotype, reverses CD8 + T cell exhaustion and is associated with recruitment of tertiary lymphoid structures (TLS) containing interferon (IFN)-stimulated/ activated B cells and germinal center B cells to enable immunotherapy efficacy and overcome resistance with long-term survival. Single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with important clinical implications. Graphical abstract
- Immunology and Microbiology
The AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes epidermal and immune homeostasis in atopic dermatitis-like skin inflammation.
In Cellular Molecular Immunology on 1 March 2025 by Chen, Z., Dragan, M., et al.
The skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonists have been approved by the FDA for psoriasis treatment and are in clinical trials for the treatment of atopic dermatitis (AD), but the underlying mechanism of action remains poorly defined. Here, we report that OVOL1/Ovol1 is a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 influences AhR-mediated regulation of keratinocyte gene expression and that OVOL1/Ovol1 ablation in keratinocytes impairs the barrier-promoting function of AhR, exacerbating AD-like inflammation. Mechanistically, weĀ have identified Ovol1's direct downstream targets genome-wide and provided in vivo evidence supporting the role of Id1 as a functional target in barrier maintenance, disease suppression, and neutrophil accumulation. Furthermore, our findings reveal that an IL-1/dermal Ī³Ī“T cell axis exacerbates type 2 and 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 functions in human AD skin. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis in the context of skin inflammation, identifying new therapeutic targets. Ā© 2025. The Author(s).
- Immunology and Microbiology,
- Pharmacology
V-domain immunoglobulin suppressor of T-cell activation and programmed death receptor 1 dual checkpoint blockade enhances antitumour immunity and survival in glioblastoma.
In British Journal of Pharmacology on 1 March 2025 by Jin, S., Li, T., et al.
The current therapy cannot meet the needs of glioblastoma (GBM). V-domain immunoglobulin suppressor of T-cell activation (VISTA) is significantly up-regulated in GBM patients; however, its therapeutic potential in GBM is still unclear. Flow cytometry was used to detect the expression of VISTA and the co-expression pattern of VISTA and programmed death receptor 1 (PD-1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of Ī±-VISTA monotherapy and Ī±-VISTA combined with Ī±-PD-1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data. Compared with normal mice, the frequency of VISTA expression and co-expression of VISTA and PD-1 on tumour-infiltrating lymphocytes (TILs) in tumour-bearing mice was increased. Anti-VISTA monotherapy significantly up-regulated multiple immune stimulation-related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD-1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8+ T cells played an important role in this process. In addition, we found that the expression of VISTA and PD-1 was significantly up-regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD-1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD-1 may achieve clinical transformation in GBM. Ā© 2024 British Pharmacological Society.
Cell atlas of human psoriasis and epidermal specific Ube2l3 deficiency mouse highlighting CXCL16/CXCR6 orchestrating the development of psoriasis
Preprint on Research Square on 28 February 2025 by Man, X., Chen, X., et al.
Abstract Psoriasis is a chronic, complex immune-mediated inflammatory disorder with cutaneous and systemic manifestations in which keratinocytes, dendritic cells and T cells have central roles. UBE2L3 may be a protective biomarker that regulates the pathogenesis of psoriasis. Here, we identified the IL-17A signaling similarity between human psoriatic skin and Ube2l3 conditional knockout mouse skin in the epidermis rather than dermis. IL-17A was regulated by CXCR6+ VĪ³2+ Ī³Ī“T in mouse while CXCR6+ CD8+ T in human. CXCL16 is the only chemokines whose bind to stimulate CXCR6. Ube2l3 reduction in keratinocytes activated IL-1Ī² and then promote CXCL16 expression through STAT3 signaling. Up-regulated CXCL16 in keratinocytes and cDC2/mDC then attracted VĪ³2+ Ī³Ī“T17 or CD8+ T to secrete IL-17A and form a positive feedback loop in keratinocytes supporting psoriatic lesion. Thus, UBE2L3 is a keratinocyte-intrinsic suppressor of epidermal IL-17 production in VĪ³2+ Ī³Ī“T in mouse and CD8+ T in human through CXCL16/CXCR6 signaling pathway in psoriasis.
- Cell Biology,
- COVID-19
IL-1Ī² drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling.
In Cell Death and Differentiation on 28 February 2025 by Bader, S. M., Scherer, L., et al.
Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse adapted SARS-CoV-2 virus and a panel of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) only marginally reduced IL-1Ī² levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (C1/11/12-/-). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1Ī², pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1Ī², but not the absence of IL-18, ameliorated disease and enhanced survival in SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate that IL-1Ī² is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways. Ā© 2025. The Author(s).
- Cancer Research,
- Immunology and Microbiology
Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8+T cells in triple-negative breast cancer
Preprint on BioRxiv : the Preprint Server for Biology on 2 February 2025 by Lim, B. J. W., Liu, M., et al.
ABSTRACT Neoadjuvant immunotherapy seeks to harness the primary tumor as a source of relevant tumor antigens to enhance systemic anti-tumor immunity through improved immunological surveillance. Despite having revolutionized the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC), a significant portion of patients remain unresponsive and succumb to metastatic recurrence post-treatment. Here, we found that optimally scheduled neoadjuvant administration of anti-4-1BB monotherapy was able to counteract metastases and prolong survival following surgical resection. Phenotypic and transcriptional profiling revealed enhanced 4-1BB expression on tumor-infiltrating intermediate (T int ), relative to progenitor (T prog ) and terminally exhausted (T term ) T cells. Furthermore, T int was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of T int , with reduced expression of tissue-retention marker CD103 in T prog . This was accompanied by increased TCR clonotype sharing between paired tumors and pre-metastatic lungs. Further interrogation of sorted intratumor T cells confirmed enhanced T cell egress into circulation following anti-4-1BB treatment. In addition, gene signature extracted from anti-4-1BB treated T int was consistently associated with improved clinical outcomes in BRCA patients. Combinatorial neoadjuvant anti-4-1BB and ablation of tumor-derived CXCL16 resulted in enhanced therapeutic effect. These findings illustrate the intratumor changes underpinning the efficacy of neoadjuvant anti-4-1BB, highlighting the reciprocity between local tissue-retention and distant immunologic fortification, suggesting treatment can reverse the siphoning of intratumor T cells to primary tumor, enabling redistribution to distant tissues and subsequent protection against metastases.
- Immunology and Microbiology
Transient Anti-TCRĪ² mAb Treatment Induces CD4 + T Cell Exhaustion and Prolongs Survival in a Mouse Model of Systemic Lupus Erythematosus.
In Immunology on 1 February 2025 by Gonzalez, N. M., Zou, D., et al.
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Chronic T cell receptor (TCR) signalling induces T cell exhaustion, characterised by reduced capacity to induce tissue damage. Here, we investigated the therapeutic potential of the anti-TCRĪ² (H57-597) monoclonal antibody (mAb) in a mouse model of SLE. Four-month-old MRL/lpr mice exhibiting SLE phenotypes received 5 weekly doses of anti-TCRĪ² mAb or phosphate-buffered saline (PBS) vehicle control. Subsequently, mouse survival was monitored daily. On day 1 post the final dose of treatment, SLE pathogenesis was determined using histological staining and spot urine test. T and B cell states in the brain, kidney, and secondary lymphoid organs were determined by flow cytometry. Transient treatment of anti-TCRĪ² mAb significantly prolonged the survival of MRL/lpr mice. Accordingly, MRL/lpr mice in the anti-TCRĪ² mAb group exhibited decreased proteinuria scores and minimal renal pathological damage compared to the PBS control group. Flow cytometric analysis revealed that anti-TCRĪ² mAb treatment resulted in a reduction in the frequencies of CD4+ T cells and CD138+B220lo/- plasma cells, plus an increase in Foxp3+ regulatory T cell frequency. Furthermore, CD4+ T cells from anti-TCRĪ² mAb treated mice exhibited elevated expression levels of PD-1 and TIM-3, with reduced IFN-Ī³ production, indicative of an exhaustion-like phenotype. Therefore, transient administration of anti-TCRĪ² mAb treatment induces an exhaustion-like phenotype in CD4+ T cells, resulting in prolonged survival of MRL/lpr mice. Inducing autoreactive T-cell exhaustion holds promise as an attractive therapeutic approach for SLE. Ā© 2024 John Wiley & Sons Ltd.
- Cardiovascular biology
Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.
In The Journal of Clinical Investigation on 30 January 2025 by Kumar, R., Nolan, K., et al.
Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment, which express the protein thrombospondin-1, which functionally activates TGF-Ī² to cause vascular disease. Blockade of monocyte recruitment with either CCL2-neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who traveled from low (225 m) to high (3500 m) elevation, revealing an increase in thrombospondin-1 and TGF-Ī² expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2+ monocyte recruitment. These data suggest a pathologic cross talk between 2 discrete interstitial macrophage populations, which can be therapeutically targeted.
- Immunology and Microbiology
Reprogramming of alveolar macrophages by intestinal segmented filamentous bacteria protects mice from lethal bacterial pneumoniae following influenza infection
Preprint on BioRxiv : the Preprint Server for Biology on 26 January 2025 by Ngo, V. L., Lieber, C. M., et al.
The most severe outcomes of respiratory viral infection (RVI) result from secondary bacterial infection, which RVI promotes via depletion of alveolar macrophages (AM). Colonization of the intestine by the common but non-ubiquitous commensal, segmented filamentous bacteria (SFB), reprograms AM to resist RVI-induced depletion. Hence, we examined if SFB against secondary infection by S. pneumoniae, H. influenzae, or S. aureus, following primary infection by influenza virus (IAV). Indeed, SFB colonization conferred strong post-IAV protection against these lethal bacterial pathogens. AM depletion and transplant studies indicated that SFB reprogramming these cells was necessary and sufficient for such protection. Assay of AM, ex vivo, from SFB-colonized mice argued their protection against secondary bacterial infection was not only due to their withstanding IAV-induced depletion. Rather, AM from SFB-colonized mice displayed complement-dependent increases in phagocytosis and killing of these bacteria. Furthermore, AM from SFB-colonized mice stably held their enhanced anti-bacterial phenotype even when transplanted into an inflamed interferon-rich post IAV-environment. Thus, SFB, and perhaps gut microbiota composition in general influences proneness to bacterial pneumonia, especially post-RVI.
- Mus musculus (House mouse)
TRAIL agonists rescue mice from radiation-induced lung, skin, or esophageal injury.
In The Journal of Clinical Investigation on 14 January 2025 by Strandberg, J., Louie, A., et al.
Radiotherapy can be limited by pneumonitis, which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found that 2 different agonists, parenteral PEGylated trimeric TRAIL (TLY012) and oral TRAIL-inducing compound (TIC10/ONC201), could reduce pneumonitis, alveolar wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22 weeks in TLY012-rescued survivors versus unrescued surviving irradiated mice. Wild-type orthotopic breast tumor-bearing mice receiving 20 Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared to be due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with the ONC201 analog ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis, and esophagitis following high doses of thoracic radiation exposure has important translational implications.
- Immunology and Microbiology
Langerhans Cells Drive Tfh and B Cell Responses Independent of Canonical Cytokine Signals
Preprint on BioRxiv : the Preprint Server for Biology on 14 January 2025 by Bouteau, A., Qin, Z., et al.
ABSTRACT Dendritic cells (DCs) are key regulators of adaptive immunity, guiding T helper (Th) cell differentiation through antigen presentation, co-stimulation, and cytokine production. However, in steady-state conditions, certain DC subsets, such as Langerhans cells (LCs), induce T follicular helper (Tfh) cells and B cell responses without inflammatory stimuli. Using multiple mouse models and in vitro systems, we investigated the mechanisms underlying steady-state LC-induced adaptive immune responses. We found that LCs drive germinal center Tfh and B cell differentiation and antibody production independently of interleukin-6 (IL-6), type-I interferons, and ICOS ligand (ICOS-L) signaling, which are critical in inflammatory settings. Instead, these responses relied on CD80/CD86-mediated co-stimulation. Our findings challenge the conventional three-signal paradigm by demonstrating that cytokine signaling is dispensable for LC-mediated Tfh and B cell responses in steady-state. These insights provide a framework for understanding homeostatic immunity and the immune systemās role in maintaining tolerance or developing autoimmunity under non-inflammatory conditions. SUMMARY STATEMENT Langerhans cells (LCs) drive germinal center Tfh and B cell responses in steady-state conditions independently of IL-6, type-I interferons, and ICOS ligand, challenging the established cytokine-centric model of T cell differentiation.
- Immunology and Microbiology
Heightened innate immune state induced by viral vector leads to enhanced response to challenge and prolongs malaria vaccine protection.
In IScience on 20 December 2024 by GbƩdandƩ, K., Ibitokou, S. A., et al.
Cytomegalovirus is a promising vaccine vector; however, mechanisms promoting CD4 TĀ cell responses to challenge, by CMV as a vector, are unknown. The ability of MCMV to prolong immunity generated by short-lived malaria vaccine was tested. MCMV provided non-specific protection to challenge with Plasmodium and increased interleukin-12 (IL-12) and CD8Ī±+ dendritic cell (DC) numbers through prolonged MCMV-dependent interferon gamma (IFN-Ī³) production. This late innate response to MCMV increased IL-12 upon challenge and increased the polyclonal CD4 effector TĀ cell response to Plasmodium, protecting in an IL-12-dependent manner. Although Plasmodium-vaccine-induced protection decayed by d200, MCMV restored protection through IFN-Ī³. Mechanistically, protection depended on MCMV-induced-IFN-Ī³ increasing CD8Ī±+ DCs and IL-12p40. MCMV expressing a Plasmodium epitope increased parasite-specific CD4 effector and effector memory TĀ cells persisting after malaria vaccination, both phenotypes reported to protect. Overall, enhanced innate cell status, a mechanism of heterologous protection by MCMV, led to a stronger TĀ cell response to challenge. Ā© 2024 The Authors.
- Cancer Research
ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages.
In Advanced Science (Weinheim, Baden-Wurttemberg, Germany) on 1 December 2024 by Du, Y., Wu, S., et al.
Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC. Ā© 2024 The Author(s). Advanced Science published by WileyāVCH GmbH.
