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dc.contributor.authorFrangieh, Chris J
dc.contributor.authorMelms, Johannes C
dc.contributor.authorThakore, Pratiksha I
dc.contributor.authorGeiger-Schuller, Kathryn R
dc.contributor.authorHo, Patricia
dc.contributor.authorLuoma, Adrienne M
dc.contributor.authorCleary, Brian
dc.contributor.authorJerby-Arnon, Livnat
dc.contributor.authorMalu, Shruti
dc.contributor.authorCuoco, Michael S
dc.contributor.authorZhao, Maryann
dc.contributor.authorAger, Casey R
dc.contributor.authorRogava, Meri
dc.contributor.authorHovey, Lila
dc.contributor.authorRotem, Asaf
dc.contributor.authorBernatchez, Chantale
dc.contributor.authorWucherpfennig, Kai W
dc.contributor.authorJohnson, Bruce E
dc.contributor.authorRozenblatt-Rosen, Orit
dc.contributor.authorSchadendorf, Dirk
dc.contributor.authorRegev, Aviv
dc.contributor.authorIzar, Benjamin
dc.date.accessioned2021-10-27T19:52:20Z
dc.date.available2021-10-27T19:52:20Z
dc.date.issued2021
dc.identifier.urihttps://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.isoen
dc.publisherSpringer Science and Business Media LLC
dc.relation.isversionof10.1038/s41588-021-00779-1
dc.rightsArticle 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.sourcebioRxiv
dc.titleMultimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion
dc.typeArticle
dc.relation.journalNature Genetics
dc.eprint.versionOriginal manuscript
dc.type.urihttp://purl.org/eprint/type/JournalArticle
eprint.statushttp://purl.org/eprint/status/NonPeerReviewed
dc.date.updated2021-07-22T14:54:02Z
dspace.orderedauthorsFrangieh, 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.submission2021-07-22T14:54:05Z
mit.journal.volume53
mit.journal.issue3
mit.licensePUBLISHER_POLICY
mit.metadata.statusAuthority Work and Publication Information Needed


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