Age as a biological stratifier for immune checkpoint inhibitor response in ovarian cancer.

BACKGROUND

Immune checkpoint inhibitor (ICI) monotherapy produces response rates of only 8-15% in ovarian cancer, widely considered ICI-refractory. However, DNA damage sensing and interferon signaling undergo pronounced age-dependent remodeling, making patient age a plausible modifier of ICI response.

METHODS

We integrated four ovarian cancer transcriptomic cohorts (n = 761) and tested the age-by-BRCA-immune interaction by pre-specified random-effects meta-analysis, comparing Young (< 50 y) versus Old (≥ 60 y) patients with the peri- and early post-menopausal transition (50-59 y) excluded from primary comparisons. Age-dependent expression of cGAS, STING1, IFI16, and IDO1 was quantified. A single-institution ICI-treated cohort (USC/LAGMC, n = 20; Responder defined as progression-free interval ≥ 365 days) provided clinical anchoring.

RESULTS

Patient age reversed the BRCA-immune relationship across all four cohorts (pooled interaction b = -0.275, 95% CI - 0.502 to - 0.048, p = 0.018, I2=0%). STING1 was reduced in older patients across three platforms (TCGA-OV FDR = 0.014; GSE9891 p = 0.0026; GSE140082 p = 6.5×10-7), together with the nuclear DNA sensor IFI16 (TCGA-OV FDR = 0.018; GSE140082 p = 0.007), while upstream cGAS was unchanged (p = 0.771). Downstream IDO1 was concurrently reduced (p = 0.009). Tumor mutational burden, HRD status, BRCA1 methylation, and an eight-gene checkpoint panel did not account for the age signal. Clinically, patients ≥ 60 y achieved 75% response versus 14% in patients < 50 y (Fisher p = 0.041), independent of BRCA status.

CONCLUSIONS

Patient age is a biological determinant of the ovarian cancer immune microenvironment through selective STING1/IFI16 attenuation with cGAS preserved. These findings support a systematic reanalysis of existing ovarian cancer ICI clinical trial data stratified by patient age.