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| Status |
Public on Dec 31, 2023 |
| Title |
Setdb1-loss induces type-I interferons and immune clearance of melanoma (scRNA-Seq) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified multiple components of the HUSH complex, including Setdb1, as hits. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERVs) in melanoma cells and triggers tumor-cell intrinsic type-I interferon signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Furthermore, spontaneous immune clearance observed in Setdb1-/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional anti-tumor role of ERV-specific CD8+ T-cells found in the Setdb1-/- microenvironment. Blocking the type-I interferon receptor in mice grafted with Setdb1-/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth comparable to Setdb1wt tumors. Together, these results indicate a critical role for Setdb1 and type-I interferons in generating an inflamed tumor microenvironment, and potentiating tumor-cell intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type-I interferon expression as potential therapeutic targets for augmenting anti-cancer immune responses.
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| Overall design |
3 tumors per condition were harvested, dissociated to single cell suspensions and tagged using HTO TotalSeq tags then pooled across condition. Samples were stained with antibodies to CD45, CD3e, CD8, Fixable Live/Dead Aqua (Life Tech), and sorted using BD FACS Aria, then pooled in the following ratios: CD45- (25%); CD45+ CD3- (25%); CD8+ (50%). 5000 cells per sample were loaded onto the 10X Chromium Library.
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| Contributor(s) |
McGeary MK, Damsky W, Daniels A, Song E, Micevic G, Huet-Calderwood C, Lou HJ, Paradkar S, Kaech S, Calderwood DA, Turk BE, Iwasaki A, Bosenberg MW |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
May 12, 2023 |
| Last update date |
Dec 31, 2023 |
| Contact name |
Meaghan McGeary |
| Organization name |
Yale School of Medicine
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| Department |
Immunobiology
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| Street address |
300 Cedar St.
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| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06511 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (15)
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| GSM7331534 |
YRG tumor, control, untreated, mRNA cDNA |
| GSM7331535 |
YRG tumor, control, untreated, scTCR cDNA |
| GSM7331536 |
YRG tumor, control, untreated, HTO-derived cDNA |
| GSM7331537 |
YRG_SETDB1-sg1 tumor, control, untreated, mRNA cDNA |
| GSM7331538 |
YRG_SETDB1-sg1 tumor, control, untreated, scTCR cDNA |
| GSM7331540 |
YRG_SETDB1-sg1 tumor, control, untreated, HTO-derived cDNA |
| GSM7331541 |
YRG_SETDB1-sg2 tumor, control, untreated, mRNA cDNA |
| GSM7331542 |
YRG_SETDB1-sg2 tumor, control, untreated, scTCR cDNA |
| GSM7331543 |
YRG_SETDB1-sg2 tumor, control, untreated, HTO-derived cDNA |
| GSM7331544 |
YRG_SETDB1-sg1 tumor, control, aIFNARtreated, mRNA cDNA |
| GSM7331546 |
YRG_SETDB1-sg1 tumor, control, a-IFNAR-treated, scTCR cDNA |
| GSM7331547 |
YRG_SETDB1-sg1 tumor, control, aIFNAR-treated, HTO-derived cDNA |
| GSM7331548 |
YRG_SETDB1-sg2 tumor, control, aIFNAR-treated, mRNA cDNA |
| GSM7331549 |
YRG_SETDB1-sg2 tumor, control, aIFNAR-treated, scTCR cDNA |
| GSM7331551 |
YRG_SETDB1-sg2 tumor, control, aIFNAR-treated, HTO-derived cDNA |
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| This SubSeries is part of SuperSeries: |
| GSE232414 |
Setdb1-loss induces type-I interferons and immune clearance of melanoma |
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| Relations |
| BioProject |
PRJNA971948 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE232413_barcodes.tsv.gz |
6.1 Mb |
(ftp)(http) |
TSV |
| GSE232413_features.tsv.gz |
284.1 Kb |
(ftp)(http) |
TSV |
| GSE232413_filtered_contig_annotations.csv.gz |
249.1 Kb |
(ftp)(http) |
CSV |
| GSE232413_matrix.mtx.gz |
34.5 Mb |
(ftp)(http) |
MTX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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