ABSTRACT
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
Subject(s)
CD8-Positive T-Lymphocytes , DNA-Binding Proteins , Interferon Type I , Membrane Proteins , Signal Transduction , Transcription Factors , Animals , Interferon Type I/metabolism , Transcription Factors/metabolism , Mice , Humans , DNA-Binding Proteins/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Neoplasms/immunology , Neoplasms/genetics , Phosphoproteins/metabolism , Exodeoxyribonucleases/metabolism , Cell Line, Tumor , Mutation , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Nuclear Proteins/metabolism , Female , Mice, Inbred C57BLABSTRACT
Pregnancy in a rudimentary uterine horn is an extremely rare form of ectopic pregnancy, with an incidence of 1 in 76,000-140,000 pregnancies. Given its high-risk nature, the standard of care is to terminate such pregnancies at the time of diagnosis. This is a case of a nulliparous patient at 23 5/7 weeks of gestation with a new diagnosis of a rudimentary horn pregnancy. She elected to proceed with full intervention for her fetus and was delivered at 24 0/7 weeks after administration of antenatal corticosteroid therapy. While the infant did have some adverse effects related to prematurity, she met developmental milestones and was alive and well at the age of two. Although the standard of care is to manage these cases as ectopic pregnancies, when diagnosed at a periviable gestational age, optimization of fetal status prior to delivery may be an alternative approach to immediate delivery.
