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Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion
dc.contributor.author | Frangieh, Chris J | |
dc.contributor.author | Melms, Johannes C | |
dc.contributor.author | Thakore, Pratiksha I | |
dc.contributor.author | Geiger-Schuller, Kathryn R | |
dc.contributor.author | Ho, Patricia | |
dc.contributor.author | Luoma, Adrienne M | |
dc.contributor.author | Cleary, Brian | |
dc.contributor.author | Jerby-Arnon, Livnat | |
dc.contributor.author | Malu, Shruti | |
dc.contributor.author | Cuoco, Michael S | |
dc.contributor.author | Zhao, Maryann | |
dc.contributor.author | Ager, Casey R | |
dc.contributor.author | Rogava, Meri | |
dc.contributor.author | Hovey, Lila | |
dc.contributor.author | Rotem, Asaf | |
dc.contributor.author | Bernatchez, Chantale | |
dc.contributor.author | Wucherpfennig, Kai W | |
dc.contributor.author | Johnson, Bruce E | |
dc.contributor.author | Rozenblatt-Rosen, Orit | |
dc.contributor.author | Schadendorf, Dirk | |
dc.contributor.author | Regev, Aviv | |
dc.contributor.author | Izar, Benjamin | |
dc.date.accessioned | 2021-10-27T19:52:20Z | |
dc.date.available | 2021-10-27T19:52:20Z | |
dc.date.issued | 2021 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/133360 | |
dc.description.abstract | © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)–Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)–JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion. | |
dc.language.iso | en | |
dc.publisher | Springer Science and Business Media LLC | |
dc.relation.isversionof | 10.1038/s41588-021-00779-1 | |
dc.rights | Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. | |
dc.source | bioRxiv | |
dc.title | Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion | |
dc.type | Article | |
dc.relation.journal | Nature Genetics | |
dc.eprint.version | Original manuscript | |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | |
eprint.status | http://purl.org/eprint/status/NonPeerReviewed | |
dc.date.updated | 2021-07-22T14:54:02Z | |
dspace.orderedauthors | Frangieh, CJ; Melms, JC; Thakore, PI; Geiger-Schuller, KR; Ho, P; Luoma, AM; Cleary, B; Jerby-Arnon, L; Malu, S; Cuoco, MS; Zhao, M; Ager, CR; Rogava, M; Hovey, L; Rotem, A; Bernatchez, C; Wucherpfennig, KW; Johnson, BE; Rozenblatt-Rosen, O; Schadendorf, D; Regev, A; Izar, B | |
dspace.date.submission | 2021-07-22T14:54:05Z | |
mit.journal.volume | 53 | |
mit.journal.issue | 3 | |
mit.license | PUBLISHER_POLICY | |
mit.metadata.status | Authority Work and Publication Information Needed |