Highlights
- Extensive dissection of non-metastatic tumor-draining lymph nodes (TDLNs-) significantly reduces progression-free survival (PFS) in patients with recurrent biliary tract cancer (BTC) receiving immunotherapy.
- Non-metastatic lymph nodes serve as a critical reservoir for TCF-1+PD-1-CD8+ tumor-specific memory T cells and CD11c+ conventional dendritic cells.
- Multiplex immunofluorescence (mIF) analysis indicates that TDLNs- possess a more favorable immune microenvironment compared to metastatic lymph nodes (TDLNs+), which are characterized by terminally exhausted T cells and regulatory T cells.
- A selective lymphadenectomy approach that preserves TDLNs- while clearing TDLNs+ may optimize outcomes for patients undergoing postoperative immunotherapy.
Background: The Evolving Role of Lymphadenectomy in the Era of Immunotherapy
Biliary tract cancer (BTC), including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer, represents a heterogeneous group of aggressive malignancies with a traditionally poor prognosis. For patients with resectable disease, radical surgery remains the primary curative intent treatment. A key component of this surgery is regional lymphadenectomy, which serves both a therapeutic purpose (clearing metastatic disease) and a diagnostic purpose (accurate staging). Current surgical guidelines often emphasize the number of lymph nodes retrieved to ensure oncological adequacy.
However, the advent of immune checkpoint inhibitors (ICIs) has necessitated a re-evaluation of the tumor-draining lymph node (TDLN). In the context of immunotherapy, lymph nodes are no longer viewed merely as potential conduits for metastatic spread, but as essential hubs for the priming, expansion, and maintenance of the anti-tumor immune response. While metastatic lymph nodes (TDLNs+) are often immunosuppressive environments, non-metastatic lymph nodes (TDLNs-) may act as vital reservoirs for immune cells that can be re-invigorated by immunotherapy. The clinical impact of removing these “clean” nodes in patients who subsequently receive immunotherapy for recurrence has remained a critical knowledge gap in surgical oncology.
Study Design: A Multicenter Real-World Analysis
To address this question, a retrospective multi-center study was conducted across five hospitals in China between 2018 and 2023. The study cohort consisted of 101 patients with recurrent BTC who were treated with immunotherapy following initial surgical resection. The primary objective was to determine whether the extent of TDLN- dissection influenced the efficacy of subsequent immunotherapy.
The study population was stratified into two groups based on the number of non-metastatic lymph nodes dissected: those with ≤6 TDLNs- and those with >6 TDLNs-. The primary endpoint was progression-free survival (PFS), with overall survival (OS) as a secondary endpoint. To provide mechanistic insight, researchers performed multiplex immunofluorescence (mIF) analysis on a subset of 20 patients from Sun Yat-sen Memorial Hospital, examining the immune microenvironment of both TDLNs- and TDLNs+.
Key Findings: Extensive Dissection Impairs Progression-Free Survival
The clinical data revealed a stark contrast in outcomes based on the extent of lymphadenectomy. Patients who underwent less extensive dissection of non-metastatic nodes (≤6 TDLNs-) achieved significantly longer PFS compared to those who had more than 6 TDLNs- removed. The hazard ratio (HR) for progression was 0.48 (95% CI, 0.31-0.73; p = 0.001), indicating a substantial reduction in the risk of recurrence or progression for the group with preserved nodes.
Interestingly, while the PFS benefit was clear, the study did not find a statistically significant difference in overall survival (OS) between the two groups. This suggests that while the initial response to immunotherapy and the duration of disease control are heavily influenced by the presence of preserved lymph nodes, other factors—such as subsequent lines of therapy and the biological heterogeneity of recurrent disease—may impact long-term survival outcomes.
Mechanistic Insights: TDLNs- as Reservoirs of Memory T Cells
The mIF analysis provided a biological explanation for the clinical findings. The researchers observed that TDLNs- and TDLNs+ are immunologically distinct environments. TDLNs- were found to contain significantly higher densities of TCF-1+PD-1-CD8+ tumor-specific memory T cells. These cells are essential for a durable response to immunotherapy because they possess high proliferative potential and can differentiate into effector cells upon re-exposure to tumor antigens.
Furthermore, TDLNs- exhibited higher concentrations of CD11c+ conventional dendritic cells (cDCs), which are critical for antigen presentation and the activation of T cells. In contrast, metastatic lymph nodes (TDLNs+) showed an unfavorable immune profile, characterized by higher proportions of FOXP3+CD4+ regulatory T cells (Tregs) and TCF-1-PD-1+CD69+CD8+ terminally exhausted T cells. These exhausted cells are typically unresponsive to PD-1/PD-L1 blockade compared to their memory counterparts.
The study also highlighted that among patients who responded to immunotherapy, the TDLNs- showed even greater densities of these beneficial memory T cells and dendritic cells. Crucially, the correlation between high memory T cell density and improved PFS was diminished in patients who underwent extensive dissection, suggesting that the physical removal of these nodes essentially “deleted” the patient’s immune reservoir.
Clinical Implications: Toward Selective Lymphadenectomy
These findings challenge the traditional “more is better” approach to lymphadenectomy in BTC, at least for patients likely to receive postoperative immunotherapy. If non-metastatic lymph nodes are essential for the efficacy of ICIs, then their indiscriminate removal may be counterproductive. The researchers propose a shift toward selective lymphadenectomy: a strategy that prioritizes the thorough clearance of clinically or pathologically involved nodes (TDLNs+) while attempting to preserve as many non-metastatic nodes (TDLNs-) as possible.
This approach requires high-precision preoperative imaging and potentially intraoperative techniques, such as sentinel lymph node mapping or rapid frozen section analysis, to distinguish between metastatic and non-metastatic nodes. By maintaining the integrity of the regional lymphatic system, surgeons may be able to provide a better “scaffold” for the patient’s immune system to respond to subsequent systemic therapies.
Expert Commentary and Limitations
This study is one of the first to provide real-world evidence of the detrimental effects of excessive TDLN- dissection on immunotherapy outcomes in BTC. However, several considerations must be noted. As a retrospective study, it is subject to inherent biases, including potential differences in surgical technique across the five participating centers and the heterogeneity of the immunotherapy regimens used. The threshold of 6 lymph nodes, while statistically significant in this cohort, may need further validation in prospective trials.
Additionally, the study focuses on recurrent BTC. The role of TDLNs in the adjuvant (post-operative, pre-recurrence) setting remains an area of intense investigation. While the preservation of nodes appears beneficial for treating recurrence, surgeons must still balance this against the risk of leaving occult micrometastases behind, which could lead to regional recurrence.
Conclusion
The research by Long et al. underscores a pivotal shift in our understanding of the relationship between surgery and immunology. In recurrent biliary tract cancer, the excessive removal of non-metastatic tumor-draining lymph nodes compromises the efficacy of immunotherapy by depleting the body’s reservoir of tumor-specific memory T cells. These findings advocate for a more nuanced, selective approach to lymphadenectomy that optimizes the synergy between surgical intervention and modern immunotherapy. As we move toward personalized medicine, the preservation of the immune microenvironment may become as important as the resection of the tumor itself.
References
Long Y, An B, Li Q, Geng Y, Zhou Y, Geng Z, Tai S, Zeng Y, Chen J, Chen Y, Zhang L. Excessive dissection of non-metastatic tumor-draining lymph nodes impairs immunotherapy efficacy in recurrent biliary tract cancer. Clin Cancer Res. 2025 Dec 29. doi: 10.1158/1078-0432.CCR-25-3296. Epub ahead of print. PMID: 41460246.
