Abstract A038: Spatial groups provide a pan-tumor spatial transcriptomic biomarker of immunotherapy response

Abstract Heterogeneity of immune checkpoint blockade (ICB) response amongst cancer patients has a profound impact on cancer-related mortality. It is now well understood that immunotherapy efficacy and resistance relate to a wide spectrum of cellular and non-cellular components in the tumor microenvironment (TME). Although the only widely used ICB biomarker, PD-L1, treats TME cells as individual components, recent work on possible biomarkers predictive of ICB response have had success by considering interactions within the TME, such as tumor cell to CD8+ T cell distances. We hypothesized that application of generalized statistical interaction approaches to tumor spatial transcriptomic datasets, which contain genome-wide information at nearly single-cell resolution, might yield novel predictive biomarkers of ICB response through leveraging TME spatial biology. Our approach was (1) to integrate spatial transcriptomics datasets from 96 tumors across twelve tumor types and (2) to apply statistical covariation approaches to identify organizing principles of spatial biology that would facilitate comparison of these datasets. Our work has identified ‘Spatial Groups’ as a conserved unit of pan-tumor spatial organization. Spatial Groups are multi-cellular units demonstrating coordinated transcriptional programs contained within spatial domains ranging in size from tens of microns (dozens of cells) to mm-scale (large regions of a tumor). These domains are hierarchically organized such that large-scale domains exert contextual field effects on nested smaller-scale domains. We found that Spatial Groups revealed immune-related spatial biology that we hypothesized might serve as a genome-wide spatial biomarker of ICB response. To test this idea, we performed a retrospective study of 16 patients with metastatic non-small cell lung cancer treated with ICB or chemotherapy-ICB in the frontline setting. We found that our Spatial Group-derived biomarker, unlike PD-L1 status, was highly significant in predicting progression-free survival after therapy initiation. Additionally, analysis of Spatial Groups in non-responder patients provided insights into patient-specific spatial biology architectures limiting ICB efficacy. In summary, our discovery of Spatial Groups provides a general framework for using spatial biology to identify pan-tumor ICB response. Citation Format: Vivek Behera, Hannah Giba, Ue-Yu Pen, Anna Di Lello, Benjamin A. Doran, Alessandra Esposito, Apameh Pezeshk, Christine M. Bestvina, Justin Kline, Marina C. Garassino, Arjun S. Raman. Spatial groups provide a pan-tumor spatial transcriptomic biomarker of immunotherapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A038.