InVivoMAb anti-mouse IFNAR-1
Product Details
The MAR1-5A3 monoclonal antibody reacts with mouse IFNAR-1 (IFN alpha/beta receptor subunit 1). IFNAR-1 is coexpressed with IFNAR-2 on nearly all cell types and together these two subunits make up the heterodimeric Type I IFN Receptor complex. Type I IFNs (IFN-Ī±/Ī²) bind to the Type I IFN Receptor complex to induce cellular responses including induction of anti-viral, anti-microbial, anti-tumor, and autoimmune responses as well as to regulate the activation, proliferation, and differentiation of many cell types. The MAR1-5A3 antibody has been shown to inhibit Type I IFN receptor signaling in vitro and in vivo.Specifications
| Isotype | Mouse IgG1,Ā Īŗ |
|---|---|
| Recommended Isotype Control(s) | InVivoMAb mouse IgG1 isotype control, unknown specificity |
| Recommended Dilution Buffer | InVivoPure pH 7.0 Dilution Buffer |
| Conjugation | This product is unconjugated. Conjugation is available via our Antibody Conjugation Services. |
| Immunogen | Extracellular domain of mouse IFNAR-1 |
| Reported Applications |
in vivo IFNAR-1 blockade in vitro IFNAR-1 blockade Western blot Flow Cytometry ELISA |
| 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 cell culture supernatant in an animal-free facility |
| Purification | Protein G |
| RRID | AB_2687723 |
| Molecular Weight | 150 kDa |
| 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 Isotype Control(s)
InVivoMAb mouse IgG1 isotype control, unknown specificity
-
Recommended Dilution Buffer
InVivoPure pH 7.0 Dilution Buffer
in vitro IFNAR-1 blockade
Falahat R, Berglund A, Perez-Villarroel P, Putney RM, Hamaidi I, Kim S, Pilon-Thomas S, Barber GN, MulƩ JJ. (2023). "Epigenetic state determines the in vivo efficacy of STING agonist therapy" Nat Commun 14(1):1573. PubMed
While STING-activating agents have shown limited efficacy in early-phase clinical trials, multiple lines of evidence suggest the importance of tumor cell-intrinsic STING function in mediating antitumor immune responses. Although STING signaling is impaired in human melanoma, its restoration through epigenetic reprogramming can augment its antigenicity and T cell recognition. In this study, we show that reversal of methylation silencing of STING in murine melanoma cell lines using a clinically available DNA methylation inhibitor can improve agonist-induced STING activation and type-I IFN induction, which, in tumor-bearing mice, can induce tumor regression through a CD8+ T cell-dependent immune response. These findings not only provide mechanistic insight into how STING signaling dysfunction in tumor cells can contribute to impaired responses to STING agonist therapy, but also suggest that pharmacological restoration of STING signaling through epigenetic reprogramming might improve the therapeutic efficacy of STING agonists.
in vitro IFNAR-1 blockade
Hosseini S, Michaelsen-Preusse K, Grigoryan G, Chhatbar C, Kalinke U, Korte M. (2020). "Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS" Cell Rep 31(7):107666. PubMed
Type I interferon receptor (IFNAR) signaling is a hallmark of viral control and host protection. Here, we show that, in the hippocampus of healthy IFNAR-deficient mice, synapse number and synaptic plasticity, as well as spatial learning, are impaired. This is also the case for IFN-Ī²-deficient animals. Moreover, antibody-mediated IFNAR blocking acutely interferes with neuronal plasticity, whereas a low-dose application of IFN-Ī² has a positive effect on dendritic spine structure. Interfering with IFNAR signaling in different cell types shows a role for cognitive function and synaptic plasticity specifically mediated by astrocytes. Intriguingly, levels of the astrocytic glutamate-aspartate transporter (GLAST) are reduced significantly upon IFN-Ī² treatment and increase following inhibition of IFNAR signaling. These results indicate that, besides the prominent role for host defense, IFNAR is important for synaptic plasticity as well as cognitive function. Astrocytes are at the center stage of this so-far-unknown signaling cascade.
in vitro IFNAR-1 blockade
Hosseini S, Michaelsen-Preusse K, Grigoryan G, Chhatbar C, Kalinke U, Korte M. (2020). "Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS" Cell Rep 31(7):107666. PubMed
Type I interferon receptor (IFNAR) signaling is a hallmark of viral control and host protection. Here, we show that, in the hippocampus of healthy IFNAR-deficient mice, synapse number and synaptic plasticity, as well as spatial learning, are impaired. This is also the case for IFN-Ī²-deficient animals. Moreover, antibody-mediated IFNAR blocking acutely interferes with neuronal plasticity, whereas a low-dose application of IFN-Ī² has a positive effect on dendritic spine structure. Interfering with IFNAR signaling in different cell types shows a role for cognitive function and synaptic plasticity specifically mediated by astrocytes. Intriguingly, levels of the astrocytic glutamate-aspartate transporter (GLAST) are reduced significantly upon IFN-Ī² treatment and increase following inhibition of IFNAR signaling. These results indicate that, besides the prominent role for host defense, IFNAR is important for synaptic plasticity as well as cognitive function. Astrocytes are at the center stage of this so-far-unknown signaling cascade.
ELISA
Lomakova YD, Londregan J, Maslanka J, Goldman N, Somerville J, Riggs JE. (2019). "PHA eludes macrophage suppression to activate CD8+ T cells" Immunobiology 224(1):94-101. PubMed
Tumors may include a high proportion of immune modulatory cells and molecules that restrain the anti-cancer response. Activation of T cells to eliminate cancer cells within the immune-suppressive tumor microenvironment remains a challenge. We have shown that C57BL/6 J peritoneal cell culture models features of macrophage-dense tumors as TCR ligation fails to activate T cells unless IFNĪ³ is neutralized or iNOS is inhibited. We tested other forms of T cell activation and found phytohemagglutinin (PHA) distinctive in the ability to markedly expand CD8 T cells in this model. IFNĪ³ or iNOS inhibition was not necessary for this response. PHA triggered less IFNĪ³ production and inhibitory PD-L1 expression than TCR ligation. Macrophages and CD44hi T cells bound PHA. Spleen T cell responses to PHA were markedly enhanced by the addition of peritoneal cells revealing that macrophages enhance T cell expansion. That PHA increases CD8 T cell responses within macrophage-dense culture suggests this mitogen might enhance anti-tumor immunity.
in vivo IFNAR-1 blockade
Macal, M., et al. (2018). "Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection" Immunity 48(4): 730-744 e735. PubMed
Although characterization of T cell exhaustion has unlocked powerful immunotherapies, the mechanisms sustaining adaptations of short-lived innate cells to chronic inflammatory settings remain unknown. During murine chronic viral infection, we found that concerted events in bone marrow and spleen mediated by type I interferon (IFN-I) and Toll-like receptor 7 (TLR7) maintained a pool of functionally exhausted plasmacytoid dendritic cells (pDCs). In the bone marrow, IFN-I compromised the number and the developmental capacity of pDC progenitors, which generated dysfunctional pDCs. Concurrently, exhausted pDCs in the periphery were maintained by self-renewal via IFN-I- and TLR7-induced proliferation of CD4(-) subsets. On the other hand, pDC functional loss was mediated by TLR7, leading to compromised IFN-I production and resistance to secondary infection. These findings unveil the mechanisms sustaining a self-perpetuating pool of functionally exhausted pDCs and provide a framework for deciphering long-term exhaustion of other short-lived innate cells during chronic inflammation.
Flow Cytometry
Troegeler A, Mercier I, Cougoule C, Pietretti D, Colom A, Duval C, Vu Manh TP, Capilla F, Poincloux R, Pingris K, Nigou J, Rademann J, Dalod M, Verreck FA, Al Saati T, Lugo-Villarino G, Lepenies B, Hudrisier D, Neyrolles O. (2017). "C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells" Proc Natl Acad Sci U S A 114(4):E540-E549. PubMed
Immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. Tuberculosis (TB) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. Here, we report that C-type lectin dendritic cell (DC) immunoreceptor (DCIR), a key component in DC homeostasis, is required to modulate lung inflammation and bacterial burden in TB. DCIR is abundantly expressed in pulmonary lesions in Mycobacterium tuberculosis-infected nonhuman primates during both latent and active disease. In mice, we found that DCIR deficiency impairs STAT1-mediated type I IFN signaling in DCs, leading to increased production of IL-12 and increased differentiation of T lymphocytes toward Th1 during infection. As a consequence, DCIR-deficient mice control M. tuberculosis better than WT animals but also develop more inflammation characterized by an increased production of TNF and inducible NOS (iNOS) in the lungs. Altogether, our results reveal a pathway by which a C-type lectin modulates the equilibrium between infection-driven inflammation and pathogen's control through sustaining type I IFN signaling in DCs.
in vivo IFNAR-1 blockade
Liu, X., et al. (2015). "CD47 blockade triggers T cell-mediated destruction of immunogenic tumors" Nat Med 21(10): 1209-1215. PubMed
Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c(+) cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.
in vivo IFNAR-1 blockade
Yang, H., et al. (2015). "STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells" Cancer Res 75(18): 3812-3822. PubMed
STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3(-/-) cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3(-/-) cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3(Y705F)) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3(-/-) cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3(-/-) and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.
in vitro IFNAR-1 blockade
Schliehe, C., et al. (2015). "The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection" Nat Immunol 16(1): 67-74. PubMed
Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and Setdb2 repressed expression of the gene encoding the neutrophil attractant CXCL1 and other genes that are targets of the transcription factor NF-kappaB. This coincided with occupancy by Setdb2 at the Cxcl1 promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone H3 Lys9 (H3K9me3). Mice with a hypomorphic gene-trap construct of Setdb2 exhibited increased infiltration of neutrophils during sterile lung inflammation and were less sensitive to bacterial superinfection after infection with influenza virus. This suggested that a Setdb2-mediated regulatory crosstalk between the type I interferons and NF-kappaB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.
in vivo IFNAR-1 blockade
Welten, S. P., et al. (2015). "The viral context instructs the redundancy of costimulatory pathways in driving CD8(+) T cell expansion" Elife 4. doi : 10.7554/eLife.07486. PubMed
Signals delivered by costimulatory molecules are implicated in driving T cell expansion. The requirements for these signals, however, vary from dispensable to essential in different infections. We examined the underlying mechanisms of this differential T cell costimulation dependence and found that the viral context determined the dependence on CD28/B7-mediated costimulation for expansion of naive and memory CD8(+) T cells, indicating that the requirement for costimulatory signals is not imprinted. Notably, related to the high-level costimulatory molecule expression induced by lymphocytic choriomeningitis virus (LCMV), CD28/B7-mediated costimulation was dispensable for accumulation of LCMV-specific CD8(+) T cells because of redundancy with the costimulatory pathways induced by TNF receptor family members (i.e., CD27, OX40, and 4-1BB). Type I IFN signaling in viral-specific CD8(+) T cells is slightly redundant with costimulatory signals. These results highlight that pathogen-specific conditions differentially and uniquely dictate the utilization of costimulatory pathways allowing shaping of effector and memory antigen-specific CD8(+) T cell responses.
in vivo IFNAR-1 blockade
Ma, Y., et al. (2014). "Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/BxN serum transfer arthritis through intrinsic control of type I IFN production" J Immunol 193(12): 6050-6060. PubMed
Localized upregulation of type I IFN was previously implicated in development of Borrelia burgdorferi-induced arthritis in C3H mice, and was remarkable due to its absence in the mildly arthritic C57BL/6 (B6) mice. Independently, forward genetics analysis identified a quantitative trait locus on Chr4, termed B. burgdorferi-associated locus 1 (Bbaa1), that regulates Lyme arthritis severity and includes the 15 type I IFN genes. Involvement of Bbaa1 in arthritis development was confirmed in B6 mice congenic for the C3H allele of Bbaa1 (B6.C3-Bbaa1), which developed more severe Lyme arthritis and K/BxN model of rheumatoid arthritis (RA) than did parental B6 mice. Administration of a type I IFN receptor blocking mAb reduced the severity of both Lyme arthritis and RA in B6.C3-Bbaa1 mice, formally linking genetic elements within Bbaa1 to pathological production of type I IFN. Bone marrow-derived macrophages from Bbaa1 congenic mice implicated this locus as a regulator of type I IFN induction and downstream target gene expression. Bbaa1-mediated regulation of IFN-inducible genes was upstream of IFN receptor-dependent amplification; however, the overall magnitude of the response was dependent on autocrine/paracrine responses to IFN-beta. In addition, the Bbaa1 locus modulated the functional phenotype ascribed to bone marrow-derived macrophages: the B6 allele promoted expression of M2 markers, whereas the C3H allele promoted induction of M1 responses. This report identifies a genetic locus physically and functionally linked to type I IFN that contributes to the pathogenesis of both Lyme and RA.
in vivo IFNAR-1 blockade
Beug, S. T., et al. (2014). "Smac mimetics and innate immune stimuli synergize to promote tumor death" Nat Biotechnol 32(2): 182-190. PubMed
Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe ācytokine storm.ā Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-beta), tumor necrosis factor alpha (TNF-alpha) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.
in vivo IFNAR-1 blockade
Calame, D. G., et al. (2014). "The C5a anaphylatoxin receptor (C5aR1) protects against Listeria monocytogenes infection by inhibiting type 1 IFN expression" J Immunol 193(10): 5099-5107. PubMed
Listeria monocytogenes is a major cause of mortality resulting from food poisoning in the United States. In mice, C5 has been genetically linked to host resistance to listeriosis. Despite this genetic association, it remains poorly understood how C5 and its activation products, C5a and C5b, confer host protection to this Gram-positive intracellular bacterium. In this article, we show in a systemic infection model that the major receptor for C5a, C5aR1, is required for a normal robust host immune response against L. monocytogenes. In comparison with wild-type mice, C5aR1(-/-) mice had reduced survival and increased bacterial burden in their livers and spleens. Infected C5aR1(-/-) mice exhibited a dramatic reduction in all major subsets of splenocytes, which was associated with elevated caspase-3 activity and increased TUNEL staining. Because type 1 IFN has been reported to impede the host response to L. monocytogenes through the promotion of splenocyte death, we examined the effect of C5aR1 on type 1 IFN expression in vivo. Indeed, serum levels of IFN-alpha and IFN-beta were significantly elevated in L. monocytogenes-infected C5aR1(-/-) mice. Similarly, the expression of TRAIL, a type 1 IFN target gene and a proapoptotic factor, was elevated in NK cells isolated from infected C5aR1(-/-) mice. Treatment of C5aR1(-/-) mice with a type 1 IFNR blocking Ab resulted in near-complete rescue of L. monocytogenes-induced mortality. Thus, these findings reveal a critical role for C5aR1 in host defense against L. monocytogenes through the suppression of type 1 IFN expression.
in vivo IFNAR-1 blockade
Stock, A. T., et al. (2014). "Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection" J Exp Med 211(5): 751-759. PubMed
Infection induces the expression of inflammatory chemokines that recruit immune cells to the site of inflammation. Whereas tissues such as the intestine and skin express unique chemokines during homeostasis, whether different tissues express distinct chemokine profiles during inflammation remains unclear. With this in mind, we performed a comprehensive screen of the chemokines expressed by two tissues (skin and sensory ganglia) infected with a common viral pathogen (herpes simplex virus type 1). After infection, the skin and ganglia showed marked differences in their expression of the family of Cxcr2 chemokine ligands. Specifically, Cxcl1/2/3, which in turn controlled neutrophil recruitment, was up-regulated in the skin but absent from the ganglia. Within the ganglia, Cxcl2 expression and subsequent neutrophil recruitment was inhibited by type I interferon (IFN). Using a combination of bone marrow chimeras and intracellular chemokine staining, we show that type I IFN acted by directly suppressing Cxcl2 expression by monocytes, abrogating their ability to recruit neutrophils to the ganglia. Overall, our findings describe a novel role for IFN in the direct, and selective, inhibition of Cxcr2 chemokine ligands, which results in the inhibition of neutrophil recruitment to neuronal tissue.
- FC/FACS,
- IHC,
- Immunology and Microbiology
Type I interferon drives T cell cytotoxicity by upregulation of interferon regulatory factor 7 in autoimmune kidney diseases in mice.
In Nature Communications on 20 May 2025 by Wang, H., Engesser, J., et al.
In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases. Ā© 2025. The Author(s).
- 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).
- In Vivo,
- Mus musculus (House mouse),
- Genetics,
- Immunology and Microbiology
A bivalent self-amplifying RNA vaccine against yellow fever and Zika viruses.
In Frontiers in Immunology on 14 May 2025 by Battisti, P., Ykema, M. R., et al.
Yellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases. YFV and ZIKV prM-E antigen-expressing saRNA constructs were created using a TC-83 strain Venezuelan equine encephalitis virus-based replicon and complexed with NLC by simple mixing. Monovalent and bivalent vaccine formulations were injected intramuscularly into C57BL/6 mice and Syrian golden hamsters, and the magnitude, durability, and protective efficacy of the resulting immune responses were then characterized. Monovalent vaccines established durable neutralizing antibody responses to their respective flaviviral targets, with little evidence of cross-neutralization. Both vaccines additionally elicited robust antigen-reactive CD4+ and CD8+ T cell populations. Notably, humoral responses to YFV saRNA-NLC vaccination were comparable to those in YF-17D-vaccinated animals. Bivalent formulations established humoral and cellular responses against both viral targets, commensurate to those established by monovalent vaccines, without evidence of saRNA interference or immune competition. Finally, both monovalent and bivalent vaccines completely protected mice and hamsters against lethal ZIKV and YFV challenge. We present a bivalent saRNA-NLC vaccine against YFV and ZIKV capable of inducing robust and efficacious neutralizing antibody and cellular immune responses against both viruses. These data support the development of other multivalent saRNA-based vaccines against infectious diseases. Copyright Ā© 2025 Battisti, Ykema, Kasal, Jennewein, Beaver, Weight, Hanson, Singh, Bakken, Cross, Fusco, Archer, Reed, Gerhardt, Julander, Casper and Voigt.
- Immunology and Microbiology
Lymphotropic Virotherapy Engages DC and High Endothelial Venule Inflammation to Mediate CancerIn SituVaccination
Preprint on MedRxiv : the Preprint Server for Health Sciences on 25 April 2025 by Ludwig, A. L., McKay, Z. P., et al.
Intratumor (IT) inoculation of the rhino:poliovirus chimera, PVSRIPO, yielded objective radiographic responses with long-term survival in 20% of patients with recurrent glioblastoma (rGBM). PVSRIPO infects dendritic cells (DCs) and sets up non-cytopathogenic viral (v)RNA replication, which triggers sustained type-I IFN (IFN-I) signaling and antitumor T cell priming. Here we identify IFN-I signaling in glioma-draining cervical lymph nodes (cLN) as a mediator of polio virotherapy. Transient IFN-I signaling after IT therapy was rescued by cervical perilymphatic injection (CPLI) of PVSRIPO, targeting cLN directly. Dual-site (IT+CPLI) PVSRIPO induced profound inflammatory reprogramming of cLN, enhanced vRNA replication and IFN-I signaling in DCs and High Endothelial Venules (HEV), augmented anti-glioma efficacy in mice, and was associated with T cell activation in rGBM patients. A Ph2 clinical trial of IT+CPLI PVSRIPO is ongoing ( NCT06177964 ). This work implicates the lymphatic system as a novel virotherapy target and demonstrates the CPLI concept to complement brain tumor immunotherapy.
- Cancer Research,
- Immunology and Microbiology
Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling.
In The Journal of Clinical Investigation on 15 April 2025 by Wei, W., Li, H., et al.
Tumor cells often employ many ways to restrain type I IFN signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulates this process remains unclear, and its effects on antitumor immunity are relatively unexplored. Here, we found that asparagine inhibited IFN-I signaling and promoted immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limited in vivo tumor growth in a CD8+ T cell-dependent manner and boosted immunotherapy efficacy. Moreover, clinically approved L-asparaginase (ASNase),synergized with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to immune checkpoint inhibitor therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.
- In Vivo,
- Mus musculus (House mouse),
- Biochemistry and Molecular biology,
- Cell Biology,
- Immunology and Microbiology
Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.
In Nature Communications on 7 February 2025 by Greene, T. T., Jo, Y., et al.
Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition. Ā© 2025. The Author(s).
- Genetics,
- Immunology and Microbiology
A bivalent self-amplifying RNA vaccine against yellow fever and Zika viruses
Preprint on BioRxiv : the Preprint Server for Biology on 4 February 2025 by Battisti, P., Ykema, M. R., et al.
ABSTRACT Introduction Yellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases. Methods YFV and ZIKV prM-E antigen-expressing saRNA constructs were created using a TC-83 strain Venezuelan equine encephalitis virus-based replicon and complexed with NLC by simple mixing. Monovalent and bivalent vaccine formulations were injected intramuscularly into C57BL/6 mice and Syrian golden hamsters, and the magnitude, durability, and protective efficacy of the resulting immune responses were then characterized. Results and discussion Monovalent vaccines established durable neutralizing antibody responses to their respective flaviviral targets, with little evidence of cross-neutralization. Both vaccines additionally elicited robust antigen-reactive CD4 + and CD8 + T cell populations. Notably, humoral responses to YFV saRNA-NLC vaccination were comparable to those in YF-17D-vaccinated animals. Bivalent formulations established humoral and cellular responses against both viral targets, commensurate to those established by monovalent vaccines, without evidence of saRNA interference or immune competition. Finally, both monovalent and bivalent vaccines completely protected mice and hamsters against lethal ZIKV and YFV challenge. We present a bivalent saRNA-NLC vaccine against YFV and ZIKV capable of inducing robust and efficacious neutralizing antibody and cellular immune responses against both viruses. These data support the development of other multivalent saRNA-based vaccines against infectious diseases.
- Cancer Research,
- Endocrinology and Physiology,
- Immunology and Microbiology
Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNĪ± and is enhanced by CD47 blockade.
In Scientific Reports on 30 January 2025 by Li, J., Luo, Y., et al.
Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16ā+āTC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on the tumor microenvironment in a transplanted B16 melanoma model, and further investigated the mechanism of action of F1/F3 using monoclonal antibodies to deplete relevant cells, gene knockout mice and flow cytometry. We show that F1/F3 is able to inhibit the growth of melanoma B16 tumour cells both in vitro and in vivo. Depletion of macrophages, blockade of IFNĪ± receptor, and Stat1 inhibition each abolishes F1/F3-mediated antitumor responses. Subsequent analysis reveals that F1/F3 increases the tumour infiltration of inflammatory macrophages, upregulates the level of IFNĪ± receptor, and promotes the secretion of IFNĪ± by macrophages. Interestingly, F1/F3 upregulates CD47 level on tumour cells; and blocking CD47 increases F1/F3-mediated antitumor responses. Furthermore, F1/F3 intratumor injection, CD47 blockade, and therapeutic vaccination significantly increases the survival time of B16 tumour-bearing mice. These results indicate that F1/F3 may be effective to improve the efficacy of ICB and therapeutic vaccine-based immunotherapy for human epithelial cancers and warrants consideration for clinical trials. Ā© 2025. The Author(s).
- Mus musculus (House mouse),
- Cancer Research
Estrogens increase cancer cell efferocytosis to establish an immunosuppressive tumor microenvironment
Preprint on BioRxiv : the Preprint Server for Biology on 26 December 2024 by Chakraborty, B., Chakraborty, P., et al.
Phagocytic clearance of apoptotic cancer cells (efferocytosis) by tumor-associated macrophages (TAMs) contributes in a substantial manner to the establishment of an immunosuppressive tumor microenvironment. This puts in context our observation that the female steroid hormone 17Ī²-estradiol (E2) facilitates tumor immune resistance through cancer cell extrinsic Estrogen Receptor (ERalpha;) signaling in TAMs. Notable was the finding that E2 induces the expression of CX3CR1 in TAMs to enable efferocytosis of apoptotic cancer cells which results in the suppression of type I interferon (IFN) signaling. Mechanistically, E2 facilitates calcium-dependent activation of the transcription factor NFATC1, which in turn induces CX3CR1 expression. This drives macrophage polarization towards an immune-suppressive state, increasing the ability of TAMs to engulf pro-inflammatory apoptotic cancer cells. Genetic or pharmacological inhibition of the E2/ER/CX3CR1 axis reversed the efferocytic activity of TAMs, rescued E2-dependent suppression of type I IFN signaling, and potentiated intratumoral adaptive immune cell function. Efferocytosis following radiation-induced cancer cell apoptosis limits the efficacy of radiation therapy. Importantly, we determined that preconditioning with either ER-directed endocrine therapies or CX3CR1 inhibition enhanced the antitumor efficacy of radiation therapy by reversing macrophage suppression and reviving intratumoral T cell activation. Our work defines the mechanisms by which E2 increases the efferocytotic activity of TAMs to establish an immunosuppressive tumor microenvironment and demonstrates how this process can be reversed with endocrine therapies which target ERalpha.
- Cancer Research,
- Genetics,
- Immunology and Microbiology
Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity.
In Science Advances on 6 December 2024 by Brodeur, M. N., Dopeso, H., et al.
Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. Damaging mutations in the SWI/SNF chromatin remodeling complex, such as SMARCA4 (BRG1), are associated with improved response to immune checkpoint blockade; however, the mechanism by which this occurs is unclear. We found that SMARCA4 loss in OC models resulted in increased cancer cell-intrinsic immunogenicity, characterized by up-regulation of long-terminal RNA repeats, increased expression of interferon-stimulated genes, and up-regulation of antigen presentation machinery. Notably, this response was dependent on STING, MAVS, and IRF3 signaling but was independent of the type I interferon receptor. Mouse ovarian and melanoma tumors with SMARCA4 loss demonstrated increased infiltration and activation of cytotoxic T cells, NK cells, and myeloid cells in the tumor microenvironment. These results were recapitulated in BRG1 inhibitor-treated SMARCA4-proficient tumor models, suggesting that modulation of chromatin remodeling through targeting SMARCA4 may serve as a strategy to overcome cancer immune evasion.
- Mus musculus (House mouse),
- Immunology and Microbiology
Boosting of CAR-T cells with rhabdovirus is limited by type I interferon and rapid contraction
Preprint on BioRxiv : the Preprint Server for Biology on 5 December 2024 by Burchett, R., Morris, C. G., et al.
Rhabdovirus vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing rhabdovirus vaccines to boost adoptively transferred T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and a personalized vaccine, which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vesicular stomatitis virus (VSV) vaccine encoding the CAR-target. Boosting CAR-engineered tumour-specific T cells with paired VSV vaccines was associated with robust T cell expansion and delayed tumour progression in syngeneic models. CAR-T cell expansion and anti-tumour function was enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with VSV encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells to achieve long-term tumour control.
- Mus musculus (House mouse),
- COVID-19,
- Genetics,
- Immunology and Microbiology
Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire.
In Proceedings of the National Academy of Sciences of the United States of America on 3 December 2024 by Abt, E. R., Lam, A. K., et al.
Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T cell responses as well as protection against lethal SARS-CoV-2 challenge in human ACE2 transgenic mice. In HLA-A2.1 transgenic mice, the RdRp vaccine elicits CD8+ T cell responses against HLA-A*02:01-restricted epitopes recognized by human donor T cells. These results highlight RdRp as a candidate antigen for COVID-19 vaccines. The findings also offer insights into crafting effective multivalent mRNA vaccines to broaden CD8+ T cell responses against SARS-CoV-2 and potentially other viruses with pandemic potential.
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
VSVāM51 drives CD8+ T cell-mediated tumour regression through infection of both cancer and non-cancer cells.
In Nature Communications on 15 November 2024 by Rajwani, J., Vishnevskiy, D. A., et al.
Oncolytic viruses (OV) are designed to selectively infect and kill cancer cells, while simultaneously eliciting antitumour immunity. The mechanism is expected to originate from infected cancer cells. However, recent reports of tumour regression unaccompanied by cancer cell infection suggest a more complex mechanism of action. Here, we engineered vesicular stomatitis virus (VSV)ĪM51-sensitive and VSVĪM51-resistant tumour lines to elucidate the role of OV-infected cancer and non-cancer cells. We found that, while cancer cell infections elicit oncolysis and antitumour immunity as expected, infection of non-cancer cells alone can also contribute to tumour regression. This effect is partly attributed to the systemic production of cytokines that promote dendritic cell (DC) activation, migration and antigen cross-presentation, leading to magnified antitumour CD8+ T cell activation and tumour regression. Such OV-induced antitumour immunity is complementary to PD-1 blockade. Overall, our results reveal mechanistic insights into OV-induced antitumour immunity that can be leveraged to improve OV-based therapeutics. Ā© 2024. The Author(s).
- Cancer Research,
- Cell Biology
Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.
In Cancer Research on 4 November 2024 by Jiao, M., Pirozzi, C. J., et al.
Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson's disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy. Ā©2024 The Authors; Published by the American Association for Cancer Research.
- Mus musculus (House mouse),
- Genetics,
- Immunology and Microbiology
Amphiphile-engineered DNA adjuvants stimulate strong type I IFN production in lymph nodes via cytosolic danger-sensing to induce potent cellular and humoral immunity in mice and non-human primates
Preprint on BioRxiv : the Preprint Server for Biology on 3 November 2024 by Steinbuck, M. P., Seenappa, L. M., et al.
ABSTRACT Adjuvants are immuno-activators capable of shaping the magnitude and quality of antigen-specific immune responses induced by subunit immunization. Presently, there is an acute need for effective adjuvants that safely induce durable and balanced humoral and cellular responses; the latter being indispensable for protection against intracellular pathogens and cancer. Here, we iteratively optimized a novel class of Amphiphile (AMP)-modified, immunostimulatory DNA-adjuvants designed for targeted delivery to lymph nodes and enhanced stimulation of cytosolic danger-sensing pathways to generate strong adaptive immunity. AMP-DNA adjuvants induced potent IFN-I-driven inflammatory environments in mouse and NHP lymph nodes that were dependent on TBK1 signaling, leading to significantly enhanced cytokine secretion by polyfunctional CD8 + and CD4 + T cells in multiple tissues, and strongly elevated T H 1-associated and neutralizing antibody responses, without toxicity. These results demonstrate that AMP-engineering enables lymph node-targeted DNA-adjuvants to uniquely activate cytosolic immune-signaling to generate robust adaptive responses crucial for vaccine efficacy.
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity.
In The EMBO Journal on 1 November 2024 by Zhou, R., Wang, M., et al.
Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b+āF4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity. Ā© 2024. The Author(s).
- In Vivo,
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
Oral reovirus reshapes the gut microbiome and enhances antitumor immunity in colon cancer.
In Nature Communications on 22 October 2024 by Lee, W. S., Lee, S. J., et al.
The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer's patch of the terminal ileum, increases IgA+ antibody-secreting cells in the lamina propria through MAdCAM-1+ blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3+ dendritic cells, type I interferons, and CD8+ T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with Ī±PD-1(L1) and/or Ī±CTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies. Ā© 2024. The Author(s).
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.
In Cancer Discovery on 4 October 2024 by Sandoval, T. A., Salvagno, C., et al.
Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell-centric modalities. Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy. See related commentary by Bell and Zou, p. 1771. Ā©2024 American Association for Cancer Research.
- Mus musculus (House mouse),
- Immunology and Microbiology
Picrasidine S Induces cGAS-Mediated Cellular Immune Response as a Novel Vaccine Adjuvant.
In Advanced Science (Weinheim, Baden-Wurttemberg, Germany) on 1 August 2024 by Ding, X., Sun, M., et al.
New adjuvants that trigger cellular immune responses are urgently needed for the effective development of cancer and virus vaccines. Motivated by recent discoveries that show activation of type I interferon (IFN-I) signaling boosts T cell immunity, this study proposes that targeting this pathway can be a strategic approach to identify novel vaccine adjuvants. Consequently, a comprehensive chemical screening of 6,800 small molecules is performed, which results in the discovery of the natural compound picrasidine S (PS) as an IFN-I inducer. Further analysis reveals that PS acts as a powerful adjuvant, significantly enhancing both humoral and cellular immune responses. At the molecular level, PS initiates the activation of the cGAS-IFN-I pathway, leading to an enhanced T cell response. PS vaccination notably increases the population of CD8+ central memory (TCM)-like cells and boosts the CD8+ T cell-mediated anti-tumor immune response. Thus, this study identifies PS as a promising candidate for developing vaccine adjuvants in cancer prevention. Ā© 2024 The Author(s). Advanced Science published by WileyāVCH GmbH.
- Mus musculus (House mouse),
- Genetics,
- Immunology and Microbiology
VHL loss enhances antitumor immunity by activating the anti-viral DNA-sensing pathway.
In IScience on 19 July 2024 by Jiao, M., Hu, M., et al.
von Hippel-Lindau (VHL), known as a tumor suppressor gene, is frequently mutated in clear cell renal cell carcinoma (ccRCC). However, VHL mutation is not sufficient to promote tumor formation. In most cases other than ccRCC, VHL loss alters cellular homeostasis and causes cell stress and metabolic changes by stabilizing hypoxia-inducible factor (HIF) levels, resulting in a fitness disadvantage. In addition, the function of VHL in regulating immune response is still not well established. In this study, we demonstrate that VHL loss enhances the efficacy of anti-programmed death 1 (PD1) treatment in multiple murine tumor models in a TĀ cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1Ī±/2Ī± induced by VHL loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA, which triggered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation and induced type I interferons. Our study thus provided mechanistic insights into the role of VHL gene loss in boosting antitumor immunity.Ā© 2024 The Authors.
