DOI: 10.5061/dryad.5mkkwh7db
title: Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

description: Isocitrate Dehydrogenase 1 (IDH1) is the most commonly mutated metabolic
 gene across human cancers. Mutant IDH1 (mIDH1) generates the
 oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in
 epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is
 T cell exclusion, whereas mIDH1 inhibition in preclinical models restores
 anti-tumor immunity. Here, we define a cell-autonomous mechanism of
 mIDH1-driven immune evasion. IDH1-mutant solid tumors show striking,
 selective hypermethylation and silencing of the cytoplasmic dsDNA sensor,
 CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA
 demethylation, derepressing CGAS and transposable element (TE) subclasses.
 dsDNA produced by TE-reverse transcriptase activates cGAS, triggering
 viral mimicry and stimulating anti-tumor immunity. Thus, we demonstrate
 that mIDH1 epigenetically suppresses innate immunity and link endogenous
 reverse transcriptase activity to the mechanism of action of an
 FDA-approved oncology drug.
description: Supplemental table for the analyses of transposable elements from
 mutant IDH1 cancer cell lines treated with mIDH1 inhibitor by two
 pipelines (TEtranscript and SQuIRE)
description: # Mutant IDH1 inhibition activates tumor immunity via endogenous reverse
 transcriptase and dsDNA sensing
 [https://doi.org/10.5061/dryad.5mkkwh7db](https://doi.org/10.5061/dryad.5mkkwh7db) Supplemental table for the analyses of transposable elements from mutant IDH1 cancer cell lines treated with mIDH1 inhibitor by two pipelines (TEtranscript and SQuIRE) # Description of the data and file structure Our new analysis demonstrates that mIDH1 ICC cells have low baseline levels of TE expression (comparable to normal liver). First, for a clear presentation of baseline TE levels, we now provide supplementary data tables with the TETranscripts family level quantification for mouse ICC (**Supplementary Data Table 2**), mouse glioma (**Supplementary Data Table 4**), human ICC (**Supplementary Data Table 6**), and human glioma (**Supplementary Data Table 8**). We used an additional approach for locus specific quantification of TEs using the SQuIRE algorithm. We also provide supplementary data tables with the SQuIRE calculated TE expression levels for each mIDH1 dataset and for a collection of normal tissue RNA-seq samples (**Supplementary Data Tables 1, 3, 4, 7**).  Each supplementary data table contains DESeq2 normalized values and DESeq2 calculated differential expression between treatment conditions. **Supplementary Data Table 1 –** SQuIRE calculated TE locus-level expression values from RNA-seq from murine CKIR132C ICC cells treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination and normal murine liver samples. Normal liver samples are downloaded from ENCODE. Counts values are DESeq2 normalized. Only TEs with average expression greater than 1 are shown. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ.  **Supplementary Data Table 2 –** TEtranscripts calculated TE family-level expression values from RNA-seq from murine CKIR132C ICC cells treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination. Counts values are DESeq2 normalized. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ. **Supplementary Data Table 3 –** SQuIRE calculated TE locus-level expression values from RNA-seq from mIDH1 primary murine glioma spheroid cells treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination and normal murine brain samples. Normal brain samples are downloaded from ENCODE. Counts values are DESeq2 normalized. Only TEs with average expression greater than 1 are shown. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ. **Supplementary Data Table 4 -** TEtranscripts calculated TE family-level expression values from RNA-seq from mIDH1 primary murine glioma spheroid cells treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination. Counts values are DESeq2 normalized. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ. **Supplementary Data Table 5 -** SQuIRE calculated TE locus-level expression values from RNA-seq from human *mIDH1* ICC cells (SNU1079) treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination and normal liver samples and a hepatocyte cell line. Normal liver and hepatocyte samples are downloaded from ENCODE. Counts values are DESeq2 normalized. Only TEs with average expression greater than 1 are shown. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ. **Supplementary Data Table 6 -** TEtranscripts calculated TE family-level expression values from RNA-seq from human *mIDH1* ICC cells (SNU1079) treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination. Counts values are DESeq2 normalized. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ. **Supplementary Data Table 7 -** SQuIRE calculated TE locus-level expression values from RNA-seq from human *mIDH1* glioma spheroids (MGG152) treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination and a collection of normal brain samples and brain tissue derived cell lines, some of which are malignant. Brain tissue samples are downloaded from ENCODE. Counts values are DESeq2 normalized. Only TEs with average expression greater than 1 are shown. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ. **Supplementary Data Table 8 -** TEtranscripts calculated TE family-level expression values from RNA-seq from human *mIDH1* glioma spheroids (MGG152) treated *in vitro* with 1 µM AG120, 10 ng/ml IFNγ, or the combination. Counts values are DESeq2 normalized. DESeq2 calculated differential expression is presented, comparing IFNγ vs DMSO, AG120 vs DMSO, and AG120+IFNγ vs DMSO. V: DMSO, I: IFNγ, A: AG120, AI: AG120+IFNγ.