Abstract A031: ECM architecture drives distinct evolutionary patterns of tumor immune escape and elimination in breast cancer
Authors: Fan Yijia , George Jason Tomas 
Published: November 2024

Cancer progression poses a clinical hurdle due to tumor heterogeneity that contributes to treatment resistance and immune evasion. While the adaptive immune system can effectively eliminate cancer in certain instances, tumor escape remains challenging. The immune microenvironment plays an important role in this process. One unanswered question is the role of ECM geometry, also known as Tumor Associated Collagen Signatures (TACS), and its effects on tumor immune recognition. In solid malignancies, ECM geometry has been associated with disease stage and T cell infiltration. Specifically, empirically observed ECM topologies are frequently categorized based on fiber arrangement: random fibers (TACS1), circumferentially aligned fibers (TACS2), and radially arranged fibers (TACS3). Even though a clear negative correlation between TACS and patient survival has been established, the specific roles and extent of TACS in T cell-driven cancer evolution remain uncharacterized. The precise mechanisms underlying how TACS influences cell movement are still not fully elucidated, with divergent opinions on whether and how the ECM mediates immune cell infiltration. At present, we currently lack a physical model relating the impact of TACS on the spatial co-evolution between an adaptive immune repertoire and a heterogeneous population of evading cancer cells. Here, we developed the EVO-ACT (EVOlutionary Agent-based Cancer T cell interaction) model, which is based on the Gillespie algorithm, to study the effects of TACS on tumor evolution and dynamical tumor-T cell interactions. Our analysis of tumor-T cell interactions across three TACS types reveals distinct migration patterns, with TACS3 showing the highest efficiency, TACS1 intermediate, and TACS2 the lowest. TACS impacts T cells more than tumors, with stronger chemokine gradients aiding T cell infiltration. Our model suggests that despite TACS2's limited efficiency, it cannot fully impede T cell infiltration. Varied migration efficiencies lead to diverse T cell infiltration patterns and immunoediting levels. TACS3 shows a benefit to immune recognition and higher survival, contrary to lower survival in TACS3 patients observed clinically in breast cancer. Our results indicate that only after introducing phenotypic changes, such as Epithelial-Mesenchymal Transition (EMT), and noting that EMT occurs exclusively after the TACS2-TACS3 progression, can our findings successfully explain the clinically observed trends. Considering mesenchymal tumor cells' ability to upregulate PD-1/PD-L1, we explore TACS-specific tumor evolution's impact on PD-1/PD-L1 inhibitor responses and patient survival. We observe higher tumor escape rates and lower survival in TACS3 compared to TACS2. Thus, TACS3 alone does not account for lower survival in breast cancer; TACS3-associated late-stage cancer byproducts like EMT and elevated checkpoint expression significantly decrease survival.

Citation Format: Yijia Fan, Jason Tomas George. ECM architecture drives distinct evolutionary patterns of tumor immune escape and elimination in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A031.