Distribution and maturity of tertiary lymphoid structures predict recurrence-free survival in cervical cancer.

[OBJECTIVE] Reliable biomarkers are needed to predict outcomes in patients with cervical cancer treated with immune checkpoint inhibitors. This study aimed to develop a novel immune classification system based on tertiary lymphoid structure maturation to stratify prognosis and PD-1 inhibitor response.

[METHODS] Surgical specimens from 451 patients with cervical cancer were analyzed to evaluate tertiary lymphoid structure spatial distribution (tumor region vs invasive margin) and maturity. Using machine learning, 4 parameters-tumor region score, invasive margin score, and tertiary lymphoid structure maturity in both regions-were integrated to establish an Immune Score-based classification (immune class I, immune class II, and immune class III). The model was validated in an external cohort of 58 PD-1 inhibitor-treated patients and compared with the International Federation of Gynecology and Obstetrics staging and combined positive score.

[RESULTS] Tertiary lymphoid structure positivity was more frequent in the invasive margin (58.2%) than in the tumor region (44.6%). All 4 tertiary lymphoid structure parameters independently predicted recurrence-free survival. The immune classification categorized patients into 3 groups with distinct 5-year recurrence-free survival rates (immune class I: 52.4%; immune class II: 78.1%; immune class III: 91.3%), outperforming International Federation of Gynecology and Obstetrics staging. In the PD-1 inhibitor cohort, higher immune class correlated with improved objective response rates (immune class I: 26.3%; immune class II: 56.3%; immune class III: 87.5%) and showed better predictive accuracy than the combined positive score. Immune class remained the only independent prognostic factor across all patient cohorts.

[CONCLUSIONS] This first tertiary lymphoid structure-based immune classification system effectively stratifies recurrence-free survival and PD-1 inhibitor response in cervical cancer, surpassing conventional staging methods. It underscores the clinical relevance of tertiary lymphoid structure organization and maturation, providing a practical tool for personalizing immunotherapy strategies.