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  3. Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer

Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer

  • Nat Immunol. 2024 Oct;25(10):1943-1958. doi: 10.1038/s41590-024-01943-5.
Christine Yiwen Yeh # 1 2 3,  Karmen Aguirre # 1 4 5,  Olivia Laveroni # 1,  Subin Kim 1,  Aihui Wang 6,  Brooke Liang 6,  Xiaoming Zhang 6,  Lucy M Han 7,  Raeline Valbuena 1,  Michael C Bassik 1,  Young-Min Kim 1,  Sylvia K Plevritis 2 8,  Michael P Snyder 1,  Brooke E Howitt 9,  Livnat Jerby 10 11 12
Affiliations

Affiliations

  • 1 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Cancer Biology Program, Stanford University, Stanford, CA, USA.
  • 5 Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 6 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 7 Department of Pathology, California Pacific Medical Center, San Francisco, CA, USA.
  • 8 Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 9 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. bhowitt@stanford.edu.
  • 10 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. ljerby@stanford.edu.
  • 11 Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. ljerby@stanford.edu.
  • 12 Chan Zuckerberg Biohub, San Francisco, CA, USA. ljerby@stanford.edu.
  • # Contributed equally.
PMID: 39179931 DOI: 10.1038/s41590-024-01943-5
Abstract

The drivers of immune evasion are not entirely clear, limiting the success of Cancer immunotherapies. Here we applied single-cell spatial and perturbational transcriptomics to delineate immune evasion in high-grade serous tubo-ovarian Cancer. To this end, we first mapped the spatial organization of high-grade serous tubo-ovarian Cancer by profiling more than 2.5 million cells in situ in 130 tumors from 94 patients. This revealed a malignant cell state that reflects tumor genetics and is predictive of T cell and natural killer cell infiltration levels and response to immune checkpoint blockade. We then performed Perturb-seq screens and identified genetic perturbations-including knockout of PTPN1 and ACTR8-that trigger this malignant cell state. Finally, we show that these perturbations, as well as a PTPN1/PTPN2 inhibitor, sensitize ovarian Cancer cells to T cell and natural killer cell cytotoxicity, as predicted. This study thus identifies ways to study and target immune evasion by linking genetic variation, cell-state regulators and spatial biology.

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