Gong and Luo et al. developed the Cancer Immunology Data Engine (CIDE) using 90 omics datasets with 8,575 profiles from 5,957 patients with 17 solid tumor types. They identified acyloxyacyl hydrolase (AOAH) as a secreted protein that enhances TCR activation and DC function by depleting immunosuppressive arachidonoyl phosphatidylcholines. AOAH overexpression, even in 10% of tumor cells, or intratumoral treatment with recombinant AOAH, boosted the efficacy of immune checkpoint blockade (ICB) and tumor infiltration with CD8+ T cells and CD11c+ DCs in mouse models. AOAH expression was higher in patients responding to ICB.
Contributed by Ute Burkhardt
ABSTRACT: Secreted proteins are central mediators of intercellular communications and can serve as therapeutic targets in diverse diseases. The ∼1,903 human genes encoding secreted proteins are difficult to study through common genetic approaches. To address this hurdle and, more generally, to discover cancer therapeutics, we developed the Cancer Immunology Data Engine (CIDE, https://cide.ccr.cancer.gov), which incorporates 90 omics datasets spanning 8,575 tumor profiles with immunotherapy outcomes from 17 solid tumor types. CIDE systematically identifies all genes associated with immunotherapy outcomes. Then, we focused on secreted proteins prioritized by CIDE without known cancer roles and validated regulatory effects on immune checkpoint blockade for AOAH, CR1L, COLQ, and ADAMTS7 in mouse models. The top hit, acyloxyacyl hydrolase (AOAH), potentiates immunotherapies in multiple tumor models by sensitizing T cell receptors to weak antigens and protecting dendritic cells through depleting immunosuppressive arachidonoyl phosphatidylcholines and oxidized derivatives.
Author Info: (1) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Department of Clin
Author Info: (1) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. (3) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (4) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (5) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. (6) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. (7) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (8) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (9) State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. (10) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (11) Office of the Director, CCR, NCI, NIH, Bethesda, MD 20892, USA. (12) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (13) Experimental Immunology Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA. (14) School of Public Health, HKU, Hong Kong, China. (15) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (16) Experimental Immunology Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA. (17) Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA. (18) Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (19) Laboratory of Integrative Cancer Immunology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (20) Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (21) WuXi Biologics, 7 Clark Drive, Cranbury, NJ 08512, USA. (22) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. Electronic address: xyguan@hku.hk. (23) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: peng.jiang@nih.gov.
