Abstract 4275: Targeting tumor extracellular matrix to improve response to therapy

Abstract Introduction. Building on our previous findings that tumor extracellular matrix (ECM) composition associates with immune cell phenotype (Pearce et al, Cancer Disco, 2018), and ECM can directly educate tumor-associated immune phenotypes (Puttock et al, Nat Commun, 2023), we present here the identification of specific ECM components that associate with tumor immune phenotype, and discuss our approach to target these components as a way to improve anti-tumor immunity and immunotherapy response. Methods. We use a combination of transcriptomics, proteomics, glycomics, and spatial tissue analysis to identify correlations between ECM composition and the immune landscape in breast and ovarian cancers. Correlations are tested within a decellularized tumor model made from patient samples which allow immune cell movement, interaction with ECM, and tumor killing to be measured in real-time. Results. Through our analysis pipeline we have identified a specific ECM molecule that appears to regulate the spatial location of tumor infiltrating CD8 T-cell populations via post-translational modifications that are present on the molecule. Deletion of this molecule in injectable orthotopic murine models dramatically alters the immune landscape within the tumor. Within an in vitro decellularized tumor tissue model the in situ deletion of the ECM molecule drives tumors into an inflamed phenotype which is more responsive to cell-based cancer therapy. Conclusions. Tumor ECM can direct immunity in two ways. These are educating or stimulating immune cells to develop specific phenotypes that tend to be immunosuppressive, and secondly directing the movement of cells within the tissue. These immunosupressive effects can be overcome through small modifications to ECM structure, indicating therapeutics that make subtle changes to ECM composition may be used in combination with current cell-based therapies to improve tumor response. Citation Format: Oliver Matthew Pearce. Targeting tumor extracellular matrix to improve response to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4275.