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
  • 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. [email protected].
  • 10. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 11. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 12. Chan Zuckerberg Biohub, San Francisco, CA, USA. [email protected].
  • # 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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