The molecular drivers preventing immune recruitment remain elusive, limiting the success of immunotherapies and cell therapies in solid tumors. Here we applied single cell spatial and perturbational transcriptomics to elucidate these processes in high-grade serous tubo-ovarian cancer (HGSC). We profiled more than 2.5 million cells in situ in 130 tumors from 94 patients, allowing us to rigorously map the spatial organization of HGSC. T and Natural Killer (NK) cells preferentially co-localize with a transcriptionally defined subset of malignant cells that is predictive T/NK infiltration levels and response to immune checkpoint blockade in diverse cancer types and is strongly associated with gene deletions and amplifications in HGSC. Perturb-seq screens identified genetic perturbations – including knockout of PTPN1 and ACTR8 – that triggered the proposed immunogenic malignant cell state identified in patients and indeed sensitize ovarian cancer cells to T and NK cell cytotoxicity. This study links genetic aberrations, malignant cell states, and immune recruitment, allowing us to identify perturbations that reprogram malignant cell states as an avenue to unleash anti-tumor immune responses.

This Single Cell Portal study (SCP2646) contains raw and processed spatial transcriptomics data associated with the “Test 2” dataset associated with the study described above. Please click through on the following links to access the other datasets associated with this study: Discovery,  Validation 1, Validation 2, and, Test 1. You can further find the associated Perturb-seq data here.

Citation: Yeh, C.Y., Aguirre, K., Laveroni, O. et al. Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer. Nat Immunol (2024). https://doi.org/10.1038/s41590-024-01943-5