Abstract
INTRODUCTION: It remains controversial regarding the prognostic impact and therapeutic implications for immunotherapy of lymph node yield (LNY) during sublobar resection (SR) on stage I lung adenocarcinoma (LUAD). METHODS: We analyzed a retrospective cohort of 400 patients with stage I LUAD who underwent SR, with peripheral blood samples prospectively collected for detecting inflammatory cytokines (IFCs). The effect of different LNY (≥4 vs. <4 nodes) on survival and IFC change was evaluated. Consensus clustering analyses were performed using data from The Cancer Genome Atlas (TCGA) and our validation cohort to explore associations between IFCs and immune/cell death profiles. A Bayesian meta-analysis was further conducted to assess the impact of LNY in LUAD undergoing SR. RESULTS: The survival analysis of our cohort demonstrated that increased LNY during SR did not prolong RFS (≥4 vs. <4 nodes: HR = 1.15; 95%CI: 0.76-1.74). A lower LNY during SR was associated with significantly better RFS in stage I LUAD receiving adjuvant immunochemotherapy (≥4 vs. <4 nodes: HR = 0.41; 95%CI: 0.17-0.94). In terms of IFCs, extensive lymph node dissection led to significantly increased levels of IL-6, IL-4, IL-10 and TNF-α after SR (p < 0.05). Consensus clustering based on the IFCs identified two subgroups (Cluster 1 and 2) in TCGA cohort with distinct immune and cell death profiles, including differences in immunogenic cell death and damage-associated molecular patterns. Cluster 2 exhibited a higher Tumor Immune Dysfunction and Exclusion (TIDE) and tumor mutation burden scores. Similar findings were observed in our validation cohort, where Cluster 2 displayed higher number of neoantigens. The Bayesian meta-analysis also corroborated that increased LNY did not improve RFS (HR = 0.98; 95%CI: 0.20-2.94) in pathological stage I LUAD. DISCUSSION: Increased LNY during SR might confer no additional benefits to RFS for p-stage I LUAD. Excessive removal of LNs might exert adverse impact on physical sensitivity to immunochemotherapy. Personalized lymph node management should be adopted for selected node-negative disease.