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.

In invasive lung adenocarcinoma (LUAD), patients with micropapillary (MIP) or solid (SOL) components had a significantly poorer prognosis than those with only lepidic (LEP), acinar (ACI) or papillary (PAP) components. It is interesting to explore the genetic features of different histologic subtypes, especially the highly aggressive components. Based on a cohort of 5,933 patients, this study observed that in different tumor size groups, LUAD with MIP/SOL components showed a different prevalence, and patients with ALK alteration or TP53 mutations had a higher probability of developing MIP/SOL components. To control individual differences, this research used spatial whole-exome sequencing (WES) via laser-capture microdissection of five patients harboring these five coexistent components and identified genetic features among different histologic components of the same tumor. In tracing the evolution of components, we found that titin (TTN) mutation might serve as a crucial intratumor potential driver for MIP/SOL components, which was validated by a cohort of 146 LUAD patients undergoing bulk WES. Functional analysis revealed that TTN mutations enriched the complement and coagulation cascades, which correlated with the pathway of cell adhesion, migration, and proliferation. Collectively, the histologic subtypes of invasive LUAD were genetically different, and certain trunk genotypes might synergize with branching TTN mutation to develop highly aggressive components.

Objectives: This study aims to explore how pre-existing conditions such as blood types, family history of cancer and comorbid diseases correlate with the genetic and programmed death-ligand 1 (PD-L1) expression that contributes to the heterogeneous biological behaviours of non-small cell lung cancer (NSCLC). Materials and methods: A cohort of 5507 NSCLC patients who underwent surgical resection between January 2014 and July 2018 was studied. Targeted next-generation sequencing was used to detect mutations in nine pivotal cancer-related genes, and immunohistochemical staining was applied to assess PD-L1 expression. Logistic regression analysis was employed to identify significant correlations. Results: All patients underwent NGS, with 1839 were also evaluated for PD-L1 expression. Several significant findings were found: ROS1 mutations were closely associated with a family history of lung cancer (OR 7.499, 95% CI 1.094 to 30.940, p=0.013). Epidermal growth factor receptor (EGFR) L858R mutations were common among patients with a family history of non-lung cancers and those with hypertension (OR 2.089, 95% CI 1.029 to 4.135, p=0.037 and OR 1.252, 95% CI 1.001 to 1.562, p=0.048, respectively). Pre-existing conditions such as diabetes and hepatitis B surface antigen positivity (OR 1.468, 95% CI 1.042 to 2.047, p=0.026 and OR 1.373, 95% CI 1.012 to 1.847, p=0.038, respectively) were correlated with EGFR exon 19 deletions. RhD negativity showed potential ties to BRAF mutations (OR 0.010, 95% CI 0.001 to 0.252, p=0.001). A history of tuberculosis linked to increased PD-L1 expression in immune cells (OR 3.597, 95% CI 1.295 to 14.957, p=0.034). Conclusion: This large-scale, cross-sectional study reveals a complex interplay between genetic mutations, immunological features and pre-existing conditions in NSCLC patients, offering insights that could inform personalised treatment strategies.