例如:"lncRNA", "apoptosis", "WRKY"

Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion.

Nat Genet. 2021 Mar;53(3):332-341. Epub 2021 Mar 01
Chris J Frangieh 1 , Johannes C Melms 2 , Pratiksha I Thakore 3 , Kathryn R Geiger-Schuller 4 , Patricia Ho 2 , Adrienne M Luoma 5 , Brian Cleary 3 , Livnat Jerby-Arnon 6 , Shruti Malu 7 , Michael S Cuoco 3 , Maryann Zhao 3 , Casey R Ager 8 , Meri Rogava 2 , Lila Hovey 3 , Asaf Rotem 9 , Chantale Bernatchez 10 , Kai W Wucherpfennig 5 , Bruce E Johnson 11 , Orit Rozenblatt-Rosen 4 , Dirk Schadendorf 12 , Aviv Regev 13 , Benjamin Izar 14
Chris J Frangieh 1 , Johannes C Melms 2 , Pratiksha I Thakore 3 , Kathryn R Geiger-Schuller 4 , Patricia Ho 2 , Adrienne M Luoma 5 , Brian Cleary 3 , Livnat Jerby-Arnon 6 , Shruti Malu 7 , Michael S Cuoco 3 , Maryann Zhao 3 , Casey R Ager 8 , Meri Rogava 2 , Lila Hovey 3 , Asaf Rotem 9 , Chantale Bernatchez 10 , Kai W Wucherpfennig 5 , Bruce E Johnson 11 , Orit Rozenblatt-Rosen 4 , Dirk Schadendorf 12 , Aviv Regev 13 , Benjamin Izar 14
+ et al

[No authors listed]

Author information
  • 1 Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 2 Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA.
  • 3 Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 4 Genentech, South San Francisco, CA, USA.
  • 5 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • 7 Immunitas Therapeutics, Waltham, MA, USA.
  • 8 Columbia Center for Translational Immunology, New York, NY, USA.
  • 9 AstraZeneca, Waltham, MA, USA.
  • 10 Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • 11 Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 12 Department of Dermatology, University Hospital Essen and German Cancer Consortium, Partner Site, Essen, Germany.
  • 13 Genentech, South San Francisco, CA, USA. aregev@broadinstitute.org.
  • 14 Program for Mathematical Genomics, Columbia University, New York, NY, USA. bi2175@cumc.columbia.edu.

摘要


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 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.