Mature Tertiary Lymphoid Structures in Breast Cancers Are Associated With Antitumor Immunity and Better Prognosis

Tertiary lymphoid structures (TLSs) are immune cells accumulated in non-lymphoid tissues, with an inner core of B cells encompassed by T cells. The aim of this study was to evaluate the clinical importance of mature TLSs in breast cancer, including their association with immunotherapy response and their role in modulating the tumor immune microenvironment. We analyzed histopathological data of 726 consecutive primary breast cancers and transcriptomic data of 824 breast cancer samples from the publicly available TCGA database to estimate the clinical and immunological value of mature TLSs in breast cancer. Additionally, we utilized pretreatment transcriptomic data of 69 breast cancer patients from the publicly available I-SPY2 clinical trial to investigate the relation between TLS-related gene signatures and patient responses to immune checkpoint inhibitors (ICIs). The existence of mature TLSs was identified in approximately 5.6% (41/726) of all breast cancer patients (HR+HER2-: 0.92%; TNBC: 14.96%; HER2+: 10.98%) and was independently associated with improved recurrence-free survival (RFS) after adjusting for subtypes, tumor-infiltrating lymphocyte (TIL) levels, and tumor stage after the multivariable Cox regression analysis in our patient cohort. Notably, the presence of mature TLSs was related to immune cell infiltration in our breast cancer patient cohort. In line with these findings, TLS-related gene signatures analyzed through transcriptomic data reliably reflected the existence of mature TLSs and were related to better clinical responses to ICIs in breast cancer patients. In conclusion, our findings show that mature TLS formation is linked with immune cell infiltration, contributes to a favorable prognosis, and may function as a potential complementary biomarker for immunotherapy response in breast cancer.