Excessive dissection of non-metastatic tumor-draining lymph nodes impairs immunotherapy efficacy in recurrent biliary tract cancer

Abstract Purpose: Non-metastatic 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 (BTC) remains unclear. We investigated the effect of TDLNs− dissection extent on treatment outcomes in this population. Methods: This real-world study retrospectively analyzed clinical and survival data from 101 recurrent BTC patients 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% CI, 0.31-0.73; p = 0.001), although there was no statistically 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 non-responders. 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. Conclusion: Excessive removal of TDLNs− compromises the efficacy of immunotherapy in recurrent BTC. A selective lymphadenectomy approach that prioritizes clearance of TDLNs+ while preserving TDLNs− may optimize outcomes for patients receiving postoperative immunotherapy.