GITR and GITR-L RNA Expression Levels Correlate with Better Survival and Response to Immunotherapy

Glucocorticoid-induced tumor necrosis factor-related protein (GITR) is an immune stimulator; however, the correlation between GITR and GITR ligand (GITR-L) expression levels and patient outcomes is not yet characterized. This study explores transcript expression patterns of GITR and GITR-L in relation to outcomes in 489 patients with advanced/metastatic cancers. Given that survival curves for the different subgroups analyzed did not show proportional hazards, restricted mean survival time (RMST) analysis was utilized. In multivariate analysis accounting for RNA expression of other immune modulators, high GITR expression correlated with better RMST in all 489 patients and in the subset of 272 patients who did not receive immunotherapy (all P < 0.05), but not in the 217 patients who received immunotherapy. On the other hand, high GITR plus low/moderate GITR-L expression correlated with longer overall survival in patients who received immunotherapy (multivariate P < 0.05), but not in the patients who did not receive immunotherapy. No GITR-correlated progression-free survival associations were observed in patients who received immunotherapy. Finally, the immunomodulator proteins inducible T-cell costimulator and CD226 were associated with a significantly improved mean survival in patients with a high GITR plus low/moderate RNA expression pattern who received immunotherapy. Overall, these results suggest that high GITR RNA expression may be independently prognostic of better RMST in patients with advanced/metastatic cancers, but only the combination of high GITR plus low/moderate GITR-L expression is independently predictive of better RMST after treatment with immunotherapy.