Elevated serum neuron-specific enolase as an indicator of poor chemo-immunotherapy outcomes and reduced CD8-positive lymphocyte infiltration in small-cell lung cancer: a retrospective cohort study

Background: Chemo-immunotherapy is the standard first-line treatment for extensive-disease small-cell lung cancer (ED-SCLC), but biomarkers for benefit remain limited. Serum neuron-specific enolase (NSE) is a classical small-cell lung cancer (SCLC) biomarker, but its relationship with the tumor immune microenvironment remains unclear. This study aimed to evaluate the association of pretreatment serum NSE with clinical outcomes and intratumoral CD8-positive lymphocyte infiltration in patients with ED-SCLC.

Methods: We retrospectively analyzed pathologically confirmed ED-SCLC patients who received first-line chemo-immunotherapy or chemotherapy. Pretreatment serum NSE was measured by electrochemiluminescence immunoassay (ECLIA). Progression-free survival (PFS) and overall survival (OS) were evaluated by NSE status. Tumor biopsy specimens were assessed for human leukocyte antigen (HLA) class I expression and CD8-positive lymphocyte infiltration. Cox models, treatment-by-NSE interaction analyses, log-transformed NSE analyses, and logistic regression for CD8 infiltration were performed.

Results: A serum NSE threshold of 64.1 ng/mL stratified patients into low- and high-NSE groups. In the chemo-immunotherapy cohort, high NSE remained independently associated with shorter PFS after adjustment for performance status (PS), stage group, liver metastasis, and brain metastasis [hazard ratio (HR), 3.68; 95% confidence interval (CI): 1.39–9.76; P=0.009]. Treatment-by-NSE interaction was significant for PFS (HR, 4.52; 95% CI: 1.27–16.10; P=0.02). CD8-positive lymphocyte infiltration was more frequent in the low-NSE group. Low NSE was independently associated with CD8-positive lymphocyte infiltration after adjustment for HLA class I expression, PS, liver metastasis, and brain metastasis [odds ratio (OR), 11.68; 95% CI: 3.01–61.32; P=0.001].

Conclusions: Pretreatment serum NSE was associated with survival outcomes and CD8-positive lymphocyte infiltration in ED-SCLC. Serum NSE may serve as a clinically accessible prognostic marker and exploratory stratification biomarker for chemo-immunotherapy benefit, particularly for PFS.