{
  "abstract": "Background Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but remains effective only in a subset of patients. A key challenge is the absence of generalizable, pan-cancer biomarkers that accurately capture tumor immune activation and predict response to ICB. Here, we present TIME_ACT, a 66-gene, unsupervised transcriptomic signature of tumor immune activation, derived from melanoma and validated across multiple cancer types and data modalities.Methods TIME_ACT was derived from TCGA melanoma by identifying genes highly upregulated in tumors classified as immune ‘hot’ based on immune score, inflammation score, and spatial TIL density. The signature was then applied across nine additional TCGA cancer types to evaluate its pan-cancer utility. Next, TIME_ACT scores were calculated for 15 independent anti-PD1 transcriptomic cohorts to evaluate their predictive power for treatment response. TIME_ACT scores were further calculated from H&E-stained pathology slides-inferred expression profiles using the deep learning models from Path2Omics, in eight new ICB clinical cohorts.Results TIME_ACT scores robustly identified immune ‘hot’ tumors across cancer types (AUC > 0.96) and positively correlated with IFN-γ signaling, cytotoxic lymphocyte abundance, and immune-rich subtypes. Spatial transcriptomics and histology-based analysis showed that TIME_ACT-high regions are enriched in lymphocyte-dense areas adjacent to tumor cells and exhibit reduced tumor-lymphocyte distances. Next, in 15 anti-PD1-treated cohorts (n = 943, six cancer types), TIME_ACT achieved a mean AUC of 0.76 and a mean odds ratio (OR) of 6.11, outperforming 22 established immune signatures and transcriptomic-based methods for ICB response prediction. Extending beyond transcriptomics, TIME_ACT scores calculated based on inferred tumor transcriptomics directly from pathology slides using Path2Omics framework accurately predicted ICB response in eight new and diverse clinical cohorts; including melanoma, NSCLC, breast, renal, bladder, and HNSCC; with a mean AUC of 0.72 and OR of 5.02, highlighting its broad clinical utility and translational potential.Conclusions TIME_ACT is a robust, pan-cancer biomarker of tumor immune activation that predicts ICB response from both transcriptomic and histopathologic data. By leveraging standard pathology slides, TIME_ACT offers a low-cost, timely, and widely accessible approach for advancing precision oncology and facilitating the effective matching of patients to ICB therapy.",
  "authors": [
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Sumit Mukherjee"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Sumeet Patiyal"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Lipika R Pal"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Tian-Gen Chang"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Sumona Biswas"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Saugatorahman R Dhruba"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Amos Stemmer"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Arashdeep Singh"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Abbas Yousefi-Rad"
    },
    {
      "affiliations": [
        "National Yang Ming Chiao Tung University, Taipei, Taiwan"
      ],
      "name": "Tien-Hua Chen"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Binbin Wang"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Denis Marino"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Wonwoo Shon"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Mark Faries"
    },
    {
      "affiliations": [
        "The Angeles Clinic and Research Institute, a Cedars Sinai Affiliate, Los Angeles, CA, USA"
      ],
      "name": "Omid Hamid"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Karen Reckamp"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Barliz Waissengrin"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Beatriz Ornelas"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Yuan Yuan"
    },
    {
      "affiliations": [
        "Taipei Veterans General Hospital, Taipei, Taiwan"
      ],
      "name": "Pen-Yuan Chu"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Salah Boudjadi"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Lisa Ley"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Dilara Akbulut"
    },
    {
      "affiliations": [
        "Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Nourhan El Ahmar"
    },
    {
      "affiliations": [
        "Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Sabina Signoretti"
    },
    {
      "affiliations": [
        "Yale School of Medicine, New Haven, CT, USA",
        "Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA"
      ],
      "name": "David A Braun"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Robert Figlin"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Hyunjeong Joo"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Hyungsoo Kim"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Arsen Osipov"
    },
    {
      "affiliations": [
        "Sheba Medical Center, Ramat Gan, Tel Aviv District, Israel"
      ],
      "name": "Jair Bar"
    },
    {
      "affiliations": [
        "Sheba Medical Center, Ramat Gan, Tel Aviv District, Israel"
      ],
      "name": "Iris Barshack"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Chi-Ping Day"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Karine Sargsyan"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Andrea B Apolo"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Kenneth Aldape"
    },
    {
      "affiliations": [
        "National Yang Ming Chiao Tung University, Taipei, Taiwan"
      ],
      "name": "Muh-Hwa Yang"
    },
    {
      "affiliations": [
        "Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA"
      ],
      "name": "Michael B Atkins"
    },
    {
      "affiliations": [
        "Cedars-Sinai Medical Center, Los Angeles, CA, USA"
      ],
      "name": "Ze’ev Ronai"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Danh-Tai Hoang"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Rockville, MD, USA"
      ],
      "name": "Eytan Ruppin"
    }
  ],
  "title": "1113 TIME_ACT: pan-cancer prediction of tumor immune activation and response to immune checkpoint blockade from tumor transcriptomics and histopathology",
  "uid": "9e7acd5b-a2d1-51b1-94e0-c8ce1bd886b8"
}