The Efficacy of Immune Checkpoint Inhibitors in the EGFR Mutant and Wild-Type Non-Small Cell Lung Cancer Is Positively Associated With the Maturation and Abundance of Dendritic Cells.

BACKGROUND

Dendritic cells (DCs) are known to be crucial in initiating immune responses, but their role in regulating immune checkpoint inhibitor (ICI) efficacy in EGFR mutant NSCLC remains unclear.

METHODS

Peripheral blood mononuclear cells (PBMCs) were co-cultured with EGFR mutant cells to evaluate immune scores and DC maturation via high-throughput sequencing. TIDE scores were used to predict the efficacy of ICI treatment. Gene set enrichment analysis (GSEA) was carried out on DCs to explore the signaling pathway changes underlying the diverse responses to ICIs.

RESULTS

A significant decrease in CD8+ T lymphocytes and cytotoxicity scores was found in EGFR mutant LUAD compared to wild-type (p < 0.001). Three datasets (GSE135222, GSE126044, and GSE136961) showed that higher DC gene expression was associated with a more favorable response to ICIs (p = 0.028). The CSE241934 dataset showed that the number of conventional DC 1 (cDC1) was higher in the ICI-sensitive group. The TIDE model suggested that cDC1 was associated with ICIs efficacy. However, GSE32863, GSE75037, and GSE72094 showed no differences in cDC subpopulations between EGFR mutant and wild-type LUAD. EGFR mutant cells exhibited more suppression in the expression of HLA-DR, CD40, CD83, and CD86 than the control group. The TIDE model suggested DC maturity was associated with ICI efficacy. GSE241934-IIT showed that DC maturity was more abundant in the ICI-sensitive group than that in the resistant group.

CONCLUSIONS

Both the number and maturation capacity of DCs are positively correlated with ICI efficacy. The cause of poor ICI efficacy in EGFR mutant LUAD is more likely to be low DC maturity, not number, compared to EGFR wild-type LUAD.