Chen et al. found that the guanosine binding autoantibody 4H2 uses nucleoside transporter-2 (ENT-2)-mediated nucleoside transport to penetrate into and localize in the cytoplasm of live cells, thus avoiding endosomes and lysosomes. 4H2 activated and promoted cGAS signaling and cGAS-dependent cytotoxicity in a nucleic acid-dependent interaction, but did not interfere with protein translation. In orthotropic GBM mouse models, systemically administered 4H2 localized to areas of necrotic tumor cells, increased T cell infiltration, and prolonged survival in a T cell-dependent manner. When injected locally, 4H2 delivered functional mRNA to cells.
Contributed by Ute Burkhardt
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.
Author Info: (1) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (3) D
Author Info: (1) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (3) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (4) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (5) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (6) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (7) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (8) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (9) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (10) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (11) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (12) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (13) Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Johnson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA. Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA. (14) Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA. Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, CA 90095, USA. (15) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (16) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.
