Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer

Abstract

Background: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear.

Methods: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy.

Results: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3_High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3_Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3_High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3_High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3_Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3_High cases than in DLL3_Low cases (4.7 vs. 7.4 months, P = 0.01).

Conclusions: Although SCLC with DLL3_High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.