DNA 损伤修复通路中的合成致死共突变预测泛癌种免疫治疗反应

Despite the significance of immune checkpoint inhibitors (ICIs) in solid tumor treatment, identifying ICI-sensitive populations remains a challenge. Mutations in DNA damage response (DDR) pathway genes are increasingly linked to favorable ICI responses; however, selection criteria for specific DDR pathway biomarkers remain elusive.

Data of patients with cancer who received ICIs and non-ICI therapy were extracted from public databases. Synthetic lethal (SL) gene combinations were selected from the SynLethDB database. Kaplan-Meier analysis was conducted to investigate the correlation between SL gene co-mutations in DDR pathways and prognosis. Immune infiltration analysis was performed using the Timer online tool based on DNA and RNA sequences obtained from The Cancer Genome Atlas database.

Patients with synthetic lethal co-mutations in DDR pathways exhibited significantly extended overall survival (HRhazard ratio [HR], 0.76 [95% CI, 0.62 to 0.92]; P = .0061), progression-free survival (HR, 0.33 [95% CI, 0.18 to 0.60]; P = .0003), and higher objective response rates (66.7% v 21.0%; P = .0009) after receiving ICIs. Conversely, DDR SL co-mut + patients receiving non-ICI treatment presented with markedly shortened survival (HR, 1.35 [95% CI, 1.16 to 1.56]; P < .0001). High-frequency DDR SL co-mutation pairs were enriched in the checkpoint factor pathway. TP53-ATM emerged as a common combination, with TP53-ATM co-mut + patients receiving more survival benefits from ICI (HR, 0.63 [95% CI, 0.41 to 0.99]; P = .045). Immune infiltration analysis demonstrated altered immune reactivity in TP53-ATM co-mut + tumors, with higher levels of CD4 + T cells, plasma cells, macrophages, natural killer cells, and myeloid dendritic cells but lower levels of CD8 + T cells.

Our study identified SL co-mutations in the DDR pathway as promising biomarkers for ICI efficacy. Specifically, the TP53-ATM co-mutation status can be applied in identifying ICI-responsive patients. SL co-mutations in DDR pathways correlate with modification of the tumor immune microenvironment, shaping a favorable niche for ICIs to stimulate immune responses.