Excessive Dissection of Nonmetastatic Tumor-Draining Lymph Nodes Impairs Immunotherapy Efficacy in Recurrent Biliary Tract Cancer

PURPOSE: Nonmetastatic tumor-draining lymph nodes (TDLNs-) are central to initiating and sustaining antitumor immunity. The impact of their surgical removal on immunotherapy efficacy in recurrent biliary tract cancer remains unclear. We investigated the effect of TDLNs- dissection extent on treatment outcomes in this population. EXPERIMENTAL DESIGN: This real-world study retrospectively analyzed clinical and survival data from 101 patients with recurrent biliary tract cancer who received immunotherapy across five Chinese hospitals (2018-2023). Patients were stratified by extent of TDLNs- dissection (≤6 vs. >6). Multiplex immunofluorescence (mIF) analysis of lymph node immune microenvironments was performed in a representative subset of patients (n = 20) from Sun Yat-sen Memorial Hospital. RESULTS: Patients with ≤6 TDLNs- dissected (n = 59) achieved significantly longer progression-free survival (PFS) than those with >6 dissected (n = 42; HR, 0.48; 95% confidence interval, 0.31-0.73; P = 0.001), although there was no statistical difference in overall survival. The mIF staining analysis revealed that TDLNs- contained higher densities of TCF-1+PD-1-CD8+ tumor-specific memory T cells and CD11c+ conventional dendritic cells and lower proportions of FOXP3+CD4+ regulatory T cells and TCF-1-PD-1+CD69+CD8+ terminally exhausted T cells compared with metastatic TDLNs (TDLNs+). Among immunotherapy responders, TDLNs- exhibited greater TCF-1+PD-1-CD8+ T-cell and CD11c+ cell densities than those in nonresponders. Importantly, a higher proportion of TCF-1+PD-1-CD8+ T cells in TDLNs- correlated with improved PFS, whereas extensive dissection of TDLNs- diminished this benefit. CONCLUSIONS: Excessive removal of TDLNs- compromises the efficacy of immunotherapy in recurrent biliary tract cancer. A selective lymphadenectomy approach that prioritizes clearance of TDLNs+ while preserving TDLNs- may optimize outcomes for patients receiving postoperative immunotherapy. See related commentary by Vonderheide, p. 2326.