Impact of lymphadenectomy extent on immunotherapy efficacy in post-resectional recurred non-small cell lung cancer: a multi-institutional retrospective cohort study

Background: Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel ‘immunotherapy-driven’ LN dissection strategy. Materials and methods: The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification. Results: A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7–13); 66 had a DLN count greater than 16 (median, IQR: 23, 19–29). With a median follow-up time of 14.3 months (95% CI: 11.0–17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1–11.7) months, 11.7 (95% CI: 7.9–15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1–6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07–0.89), P =0.03]; [validation cohort: HR=0.46 (95% CI: 0.22–0.96), P =0.04]; [entire cohort: HR=0.53 (95% CI: 0.32–0.89), P =0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065–0.845, P =0.027). Conclusions: An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.