Synthetic Lethal Co-Mutations in DNA Damage Response Pathways Predict Response to Immunotherapy in Pan-Cancer.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.