Abstract 7495: The evolving ECM architecture shapes unique evolutionary trajectories of breast tumor immune escape and elimination

Abstract Purpose: Cancer progression remains a clinical challenge due to tumor heterogeneity. Effective T cell infiltration is critical for mounting an anti-tumor response. Tumors are classified as “hot” or “cold” based on the extent of T cell infiltration. In many cancers, particularly breast cancer, extracellular matrix (ECM) geometry evolves with tumor progression, characterized by Tumor-Associated Collagen Signatures (TACS). Specifically, empirically observed ECM topologies are random fibers (TACS1), circumferentially aligned fibers (TACS2), and radially arranged fibers (TACS3). Clinically, patients with TACS3+ breast cancer exhibit poorer survival compared to TACS3- cases, but the underlying mechanisms and the role of evolving ECM geometry in tumor evolution and tumor-T cell interaction remain unclear. The lack of biomarkers or methods to track TACS evolution underscores the need for physical models linking ECM geometry to tumor-immune co-evolution. Methods: To address this, we developed the EVO-ACT (EVOlutionary Agent-based Cancer T cell interaction) model, built upon the Gillespie algorithm. Results: Our analysis of the three TACS geometries revealed distinct T cell migration patterns and efficiencies: TACS3 demonstrated the highest efficiency, TACS1 intermediate, and TACS2 the lowest. While TACS geometry significantly influences T cell infiltration, it does not act as an absolute barrier; stronger chemokine gradients enhance T cell infiltration across all TACS types. Notably, TACS3 facilitates immune recognition and correlates with higher survival in our simulations, which contrasts with the clinically observed lower survival of TACS3+ breast cancer patients. As TACS3 is typically linked to late-stage breast tumors with phenotypic adaptations, we incorporated mechanisms such as EMT into our model to address this discrepancy. The progression from TACS2 to TACS3, coupled with EMT, more accurately reproduced clinical outcomes. Considering the mesenchymal phenotype’s ability to upregulate immune checkpoint molecules such as PD-1/PD-L1, we further explored TACS-specific tumor evolution and its impact on responses to immune checkpoint inhibitors and patient survival. Our findings reveal lower survival in TACS3/EMT+/PD-L1+ cases compared to TACS2/EMT-/PD-L1+ cases, highlighting that TACS3-associated poor survival arises not solely from ECM geometry but from late-stage cancer adaptations such as EMT and upregulated immune checkpoint expression. Conclusions: This study underscores the complex interplay between evolving ECM geometry and tumor-T cell interaction dynamics, offering a new explanation for TACS-associated survival differences. It also provides novel insights into TACS-specific responses to PD-1/PD-L1 inhibitors and their implications for patient survival. Citation Format: Yijia Fan, Jason Tomas George. The evolving ECM architecture shapes unique evolutionary trajectories of breast tumor immune escape and elimination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7495.