404MO Tertiary lymphoid structures localization and maturation heterogeneities correlate with divergent microenvironment features and immune responses of clear cell renal cell carcinoma

Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that form postnatally in non-lymphoid tissues and arise under pathological conditions. The prognostic and predictive value of TLS in the tumor microenvironment (TME) has strengthened interest as potential mediators of antitumor immunity. Immunohistochemistry and multispectral fluorescent were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. We comprehensively assessed the prognostic and immunological implications of the TLS heterogeneity in 625 patients with ccRCC from multiply cohorts. Associations between TLS heterogeneity and immunologic activities were assessed by the quantification of immune cells infiltration. TLS typically comprises B-cell follicles with germinal centers and are surrounded by T-cell zones and dendritic cells. TLS infiltrates were identified in 34.2% of the ccRCC samples, with intratumoral, peritumoral, and both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in peritumoral TLS (P=0.016), while intratumoral TLS mainly comprised secondary follicle-like (P=0.004). Kaplan-Meier analyses indicated that the presence of mature TLS (namely SFL-TLS, with CD23+ germinal center) markedly correlated with both better survival. Notably, presence of TLS, especially intratumoral TLS and SFL-TLS significantly correlated with better survival and objective reflection rate for ccRCC patients receiving anti-PD-1/PD-L1 immunotherapies. Interestingly, in ccRCC samples with the presence of peritumoral TLS enriched with primary follicle-like TLS, the proportion of tumor-associated macrophages and Treg infiltration in the peritumoral regions increased prominently, showing a typical suppressive TME characterizations. In conclusion, this study for the first time revealed the implications of TLS localization and maturation heterogeneity on the immunological status and responses of ccRCC, allowing the identification of immunophenotypes and the improvement of immunotherapeutic effectiveness for ccRCC.