三级淋巴结构评分与三阴性乳腺癌中独特的免疫特征和治疗反应相关

Background: Tertiary lymphoid structures (TLSs) are aggregates of immune cells that resemble secondary lymphoid organs in both morphology and function, and are frequently observed within the tumor microenvironment (TME) of solid cancers including breast cancer. TLS have emerged as a predicter of anti-tumor immune activation and improved responses to immune checkpoint inhibitors (ICIs). However, TLS evaluation typically relies on histology that limits its generalizability. We hypothesize that TLS score is associated with distinct immune profiles and therapeutic response in triple negative breast cancer. Methods: Clinical and transcriptomic data from 12 independent TNBC cohorts (TCGA(n=170), METABRIC(n=335), SCAN-B(n=174), GSE194040(n=363), GSE25066(n=133), GSE163882(n=90), GSE123845(n=86), GSE20271(n=63), GSE50948(n=17), GSE230881(n=49), GSE41998(n=151), GSE176078(n=10)) were analyzed using established 12-gene TLS signature score. The patients in each cohort were divided into TLS-high and low groups by median cutoff. For validation of the TLS score, we utilized pathological and spatial transcriptomic data from GSE17703(n=30) and EGAC50000000323(n=96). Associations between the TLS score and clinicopathologic features, genomic features and therapeutic outcomes were assessed. Results: The TLS score was significantly higher in tumors with histologically confirmed TLSs. Spatial transcriptomic analysis revealed that high TLS scores colocalized with histologically confirmed TLSs, suggesting that the TLS score reliably reflects the presence of TLS. High-TLS score tumor had higher histological grade and lymph node involvement, and associates with significant enrichment of Hallmark cell proliferation-related pathways. Immune-related pathways were also significantly enriched in the TLS-high group, which exhibited significantly greater infiltration of CD8+ T cells, B cells, regulatory T cells, macrophage M1, and dendric cells. Among immune cells, macrophages displayed particularly elevated TLS scores, and TLS-high immune cells showed stronger intercellular communication. TLS scores were not associated with HRD or mutation burden, however, TLS-high tumors showed higher intratumoral genomic heterogeneity, suggesting that they are genomically stable yet immunologically inflamed and likely to be aggressive. Across 8 independent neoadjuvant chemotherapy cohorts, TLS scores were significantly higher in patients who achieved pathological complete response, with the largest effect observed in the ICI-treated cohort. Despite their association with features of aggressive biology, TLS-high tumors demonstrated more favorable clinical outcomes. Conclusions: TLS-high TNBC were highly proliferative but immunologically active, and the TLS score was strongly associated with better treatment response and improved prognosis.