2025-03-25 イェール大学
<関連情報>
- https://medicine.yale.edu/news-article/lupus-related-antibody-shows-promise-in-enhancing-cancer-treatment-efficacy/
- https://www.science.org/doi/10.1126/scisignal.adk3320
細胞内RNAに結合するループス由来の自己抗体が、cGASを介する腫瘍免疫を活性化し、RNAを細胞内に送り込むことができる A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells
Xiaoyong Chen, Xiangjun Tang, Ying Xie, Benedette J. Cuffari, […] , and James E. Hansen
Science Signaling Published:25 Mar 2025
DOI:https://doi.org/10.1126/scisignal.adk3320
Editor’s summary
Many cancers suppress immune surveillance and resist immune-targeted therapies. Chen et al. found that antitumor immunity and treatment might be improved by harnessing an antibody associated with the autoimmune disease lupus. The antibody, called 4H2, was taken up into cells where it bound to endogenous (“self”) RNA to recruit and activate the nucleic acid sensor cGAS, which initiated inflammatory signaling that was cytotoxic to brain, lung, and breast cancer cells in culture but not to normal breast epithelial cells. In mice with glioblastomas, 4H2 localized to the tumor microenvironment after systemic administration, improved animal survival in a T cell–dependent manner, and improved the efficacy of immune checkpoint blockade therapy, demonstrating its potential for treating patients. —Leslie K. Ferrarelli
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.
