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A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver
Xiaoyong Chen1, Xiangjun Tang2, Ying Xie2
1Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA.
Abstract:
Nucleic acid-mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody entered cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and bound to endogenous RNA in live cells. In orthotopic models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on T cells. Mechanistic studies revealed that antibody binding to nucleic acids activated the cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody-nucleic acid interaction that is translatable to strategies for nonviral gene delivery and immunotherapy.
Insights
A novel antiguanosine autoantibody, linked to systemic lupus erythematosus (SLE), targets cancer cells by binding RNA and activating immune responses. This discovery opens new avenues for cancer immunotherapy and nonviral gene delivery.
Area of Science:
- Immunology
- Autoimmunity
- Cancer Biology
Background:
- Nucleic acid signaling is implicated in autoimmune diseases like systemic lupus erythematosus (SLE).
- Autoantibodies in SLE may offer unexpected therapeutic applications.
Purpose of the Study:
- To investigate the therapeutic potential of an SLE-associated antiguanosine autoantibody in cancer treatment.
- To elucidate the mechanism of action and cellular entry of this autoantibody.
Main Methods:
- Utilized cell-penetrating autoantibodies in orthotopic glioblastoma models.
- Investigated antibody-nucleic acid interactions within live cells and in vivo.
- Analyzed immune activation via cyclic GMP-AMP synthase (cGAS) pathway.
Main Results:
- The autoantibody entered cells via a non-endosomal pathway and bound endogenous RNA.
- In glioblastoma models, the antibody promoted T cell-dependent survival.
- Antibody-RNA binding activated cGAS, leading to immune signaling and tumor cell death.
- The autoantibody facilitated functional RNA delivery into various tissues.
Conclusions:
- An antiguanosine autoantibody can engage intracellular RNA to activate anti-tumor immunity.
- This autoantibody-nucleic acid interaction presents a novel strategy for cancer immunotherapy.
- The findings support the translation of this approach for nonviral gene delivery.
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