Abstract C037: Tertiary lymphoid structures as a prognostic indicator independent of tumor-infiltrating lymphocytes and tumor mutational burden in microsatellite instability-high colorectal cancer

Abstract Background: Tertiary lymphoid structures (TLSs) are increasingly recognized as key contributors to antitumor immunity. However, their prognostic relevance and their relationships to other major immune and molecular features, including tumor-infiltrating lymphocytes (TILs) and tumor mutational burden (TMB), remain incompletely defined. Here, we investigated the clinical, molecular, and immunologic implications of TLSs in colorectal cancer (CRC) with microsatellite instability-high (MSI-H). Methods: TLS density and diameter were quantified using digital pathology–based whole-slide images of hematoxylin and eosin–stained tumor sections from two independent cohorts of curatively resected MSI-H CRC (discovery, n=133; validation, n=116). Prognostic value was evaluated using univariate and multivariate analyses of disease-free survival. Quantitative immunohistochemistry for CD3+/CD8+ TILs and whole-exome and transcriptome sequencing were performed to assess associations between TLS metrics and tumor immunologic or molecular characteristics. Results: Both TLS density and maximum TLS diameter were significant prognostic factors independent of the CD3+/CD8+ TIL immunoscore in each cohort. These TLS features were associated with relative enrichment of B-cell and T-cell subsets within the tumor microenvironment. No significant associations were observed between prognostic TLS parameters and major tumor molecular characteristics, including TMB, driver mutations, consensus molecular subtype, or CpG island methylator phenotype. Conclusions: TLSs constitute an independent prognostic factor in MSI-H CRC. Our findings suggest that activated TLSs may reflect integrated B-cell– and T-cell–mediated antitumor immunity that operates independently of TIL density and TMB. Declaration of Use of Generative AI: ChatGPT was used to improve readability and language during the preparation of this abstract. Citation Format: Jung Ho Kim, Jiyun Hong, Sangwoo Kim, Minsun Jung. Tertiary lymphoid structures as a prognostic indicator independent of tumor-infiltrating lymphocytes and tumor mutational burden in microsatellite instability-high colorectal cancer abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C037.