Mature Tertiary Lymphoid Structures Indicate Good Chemotherapy Response and Prognosis in Advanced Colorectal Cancer

ABSTRACT Background Tertiary lymphoid structures (TLS), clusters of immune cells including B and T cells, are involved in anti‐tumor immunity and correlate with a favorable prognosis in several malignancies, but their association with systemic chemotherapy is unknown. We investigated the role of TLS as a biomarker for predicting chemotherapy efficacy in advanced colorectal cancer (CRC). Methods We analyzed 78 CRC cases with metastatic or recurrent lesions, in which untreated resected primary tumors were available before chemotherapy. TLS maturity, defined by the presence of CD23 + B cells in germinal centers, was assessed by immunohistochemistry and evaluated in relation to clinicopathological features, treatment response, tumor‐infiltrating lymphocytes, and prognosis. In 11 cases with resected metastatic lesions, tumor‐infiltrating lymphocytes were analyzed to explore the relationship between TLS maturity in primary tumors and immune status at distant sites. Results Mature TLS‐negative groups had poorer chemotherapy sensitivity, progression‐free survival, and overall survival. Multivariate analysis confirmed TLS maturity as an independent predictor of both therapeutic response and survival outcomes in this cohort. Mature TLS was associated with higher CD3 + and CD8 + T‐cell infiltration in both primary and metastatic tumors. Conclusion Mature TLS may contribute to favorable chemotherapeutic efficacy through immune activity. TLS maturity in primary tumors may represent a novel biomarker for predicting systemic chemotherapy response and immune status across primary and metastatic sites in advanced CRC.