Abstract A099: The IO-Atlas Project: A cross-cohort tumor immunophenotyping platform enhancing precision immuno-oncology

Abstract The tumor microenvironment (TME) is complex and significantly influences how patients respond to immunotherapy. Despite decades of research generating numerous gene signatures to describe the TME, there is no consensus on the best way to capture meaningful variation, as the commonly used gene signatures are heavily T cell-biased with high degrees of collinearity. To better understand TME dynamics and represent them consistently and interpretably, we developed a framework for immunophenotyping using disparate immuno-oncology (IO) transcriptional “fingerprints” as part of the AbbVie IO Atlas Project. This framework provides a concise and informative representation of the TME by refining previously published TME gene expression signatures. Using the framework, we integrated bulk RNAseq profiles from two pan-cancer patient cohorts—The Cancer Genome Atlas (TCGA) and a real-world cohort (Aster Insights’ Avatar)—by representing these samples with IO fingerprints, which generated a cross-tumor and cross-dataset representation of the TME across a broad patient spectrum. This integration mitigates the limitation of TCGA data alone by combining treatment-naïve and early-stage cancers with heavily pre-treated, later-stage, and metastatic cancers. Consequently, the IO-centric sample relationships enabled us to identify cross-cohort IO subpopulations within individual tumor indications. Furthermore, by representing tumor profiles from patients treated with immune checkpoint inhibitors, we uncovered novel patient subpopulations with distinct IO fingerprint patterns, which were associated with ICI responses in lung adenocarcinoma and clear cell renal cell carcinoma. By delving into the paired molecular profiles of these patients, we hypothesized the underlying mechanisms driving response or non-response and suggested novel strategies to address the unmet medical needs of patient subpopulations treated with existing IO regimens. Our findings demonstrate that the comprehensive integration of diverse patient data using the IO Atlas framework can lead to more effective immunotherapy strategies. AbbVie Disclosure Statement: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Liqian Ma, Jacob Pfeil, Hin-Ching Lo, Tolga Turan, Sarah Kongpachith, Xi Zhao, Josue Samayoa, Kyle Halliwill. The IO-Atlas Project: A cross-cohort tumor immunophenotyping platform enhancing precision immuno-oncology [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A099.