A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

Cuffari

et al. 2023

Preprint

Cytoplasmic DNA triggers a cGAS-mediated signaling cascade that promotes an innate immune response and is potentially actionable in cancer immunotherapy. Here we show that a cytoplasmic-localizing lupus anti-DNA autoantibody activates cGAS and facilitates an immune-mediated prolongation of survival in orthotopic models of glioblastoma (GBM). Mechanistically, cellular penetration and blood-brain barrier crossing by the anti-DNA autoantibody is linked to nucleoside transport. Pulldown, knockdown, signaling, and cytotoxicity assays demonstrate autoantibody association with and activation of cGAS. In orthotopic GBM models, the autoantibody localizes to brain tumor, increases tumor CD8+ T cell content, and prolongs survival in immunocompetent but not immunodeficient mice. This work introduces the new concept of a cGAS-activating anti-DNA autoantibody, which impacts theories on mechanisms of autoimmunity and has translational applications in cancer immunotherapy.

Section: Introductionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

cGAS-activating lupus autoantibody for cancer immunotherapy

Cuffari

et al. 2023

Preprint

“…The IFN-I signaling pathway is the primary defense mechanism for the host against HSV-1 infection [ 63 ]. As depicted in Figure 3 , HSV-1 infection activates Toll-like receptors (TLRs), retinoic acid-inducible gene l-like receptors (RLRs), and DNA receptor cyclic GMP-AMP synthase (cGAS) via PAPMs (including viral capsids, nucleic acids, or proteins), which in turn induce the production of IFN-I [ 64 , 65 , 66 , 67 ]. Among them, TLR2 [ 68 ], TLR3 [ 69 ], and TLR9 [ 70 ] recognize HSV-1 and activate antiviral responses.…”

Section: Potential Hsv-1 Immune Clearance Problems In Intravenous Adm...mentioning

confidence: 99%

The Dilemma of HSV-1 Oncolytic Virus Delivery: The Method Choice and Hurdles

Wang

Zhao

et al. 2023

IJMS

Self Cite

Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 (HSV-1) is the most commonly used. However, the current mode of administration of HSV-1 oncolytic virus is mainly based on the tumor in situ injection, which limits the application of such OV drugs to a certain extent. Intravenous administration offers a solution to the systemic distribution of OV drugs but is ambiguous in terms of efficacy and safety. The main reason is the synergistic role of innate and adaptive immunity of the immune system in the response against the HSV-1 oncolytic virus, which is rapidly cleared by the body’s immune system before it reaches the tumor, a process that is accompanied by side effects. This article reviews different administration methods of HSV-1 oncolytic virus in the process of tumor treatment, especially the research progress in intravenous administration. It also discusses immune constraints and solutions of intravenous administration with the intent to provide new insights into HSV-1 delivery for OV therapy.

“…Although it has been initially characterized in pathogen-infected cells, activation of IFN-I is now a well-established cellular response to damage-associated molecular patterns, which are abnormal molecules in the cytosolic compartment. These abnormal molecules include leaked fragments of nuclear DNA and mitochondrial DNA and dsRNA. , A recent report by Marzio et al (2022) provided strong evidence from experimental models and human clinical studies that INF-I response is regulated by KEAP1 as a separate function from its control of NRF2. Similar to its regulation of NRF2 in unstressed cells, KEAP1 was found to target a proto-oncogene EMSY for ubiquitin-mediated proteasomal degradation.…”

Section: Stress-regulated Immunosurveillance Of Damaged Cellsmentioning

confidence: 99%

“…These abnormal molecules include leaked fragments of nuclear DNA and mitochondrial DNA and dsRNA. 100 , 101 A recent report by Marzio et al (2022) 33 provided strong evidence from experimental models and human clinical studies that INF-I response is regulated by KEAP1 as a separate function from its control of NRF2. Similar to its regulation of NRF2 in unstressed cells, KEAP1 was found to target a proto-oncogene EMSY for ubiquitin-mediated proteasomal degradation.…”

Section: Stress-regulated Immunosurveillance Of Damaged Cellsmentioning

confidence: 99%

HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System

Cyran

Zhitkovich

2022

Chem. Res. Toxicol.

Cellular homeostasis is continuously challenged by damage from reactive oxygen species (ROS) and numerous reactive electrophiles. Human cells contain various protective systems that are upregulated in response to protein damage by electrophilic or oxidative stress. In addition to the NRF2mediated antioxidant response, ROS and reactive electrophiles also activate HSF1 and HIF1 that control heat shock response and hypoxia response, respectively. Here, we review chemical and biological mechanisms of activation of these three transcription factors by ROS/reactive toxicants and the roles of their gene expression programs in antioxidant protection. We also discuss how NRF2, HSF1, and HIF1 responses establish multilayered cellular defenses consisting of largely nonoverlapping programs, which mitigates limitations of each response. Some innate immunity links in these stress responses help eliminate damaged cells, whereas others suppress deleterious inflammation in normal tissues but inhibit immunosurveillance of cancer cells in tumors.