The prognostic and predictive value of the immunological gene signatures interferon gamma and TIDE for patients with liver metastases from uveal melanoma treated with isolated hepatic perfusion.

Abstract

e21596 Background: Uveal melanoma (UM) is a rare cancer that often metastasizes to the liver. The SCANDIUM trial investigated the efficacy of isolated hepatic perfusion (IHP) using a single high dose of melphalan in treating metastatic UM. IHP may induce an immunogenic type of cell death induced by the alkylating agent melphalan, and this may serve as a secondary mechanism of action for the IHP treatment. Assessment of baseline tumor transcriptomic signatures is a promising strategy for predicting treatment response and prognosis. We hypothesize that a tumor’s immunological status at baseline could be predictive of treatment response and outcome of IHP in metastatic UM. Methods: In this retrospective analysis, we analyzed immunological gene signatures derived from the baseline transcriptomic profiles of liver metastases in 27 patients treated with IHP. Response was evaluated on CT scans according to RECIST 1.1 criteria, classifying patients as responders (CR, PR) or non-responders (SD, PD) based on their best overall response. Samples from 22 patients that passed quality control were used for analysis. Scores for interferon gamma (IFNG), tumor immune dysfunction and exclusion (TIDE) and related immune and stromal signatures were calculated using the TIDE framework via its Python implementation (TIDEpy). The median score was used as a cutoff for patient stratification in survival analysis. Log-rank test was used to compare survival distributions and Wilcoxon rank sum test was used to compare signatures between responders and non-responders. Results: TIDE signature was significantly increased in non-responders compared to responders (p < 0.001) while IFNG signature showed no difference. Out of the two TIDE components, the immune dysfunction and exclusion signatures, exclusion was higher in non-responders but not significant (p = 0.051), while dysfunction remained unchanged. This highlights the impact of the tumor microenvironment's immune suppression on response following IHP treatment. Kaplan-Meier survival analysisshowed that patients with a lower TIDE score had increased progression-free survival (PFS), with a median of 10.3 vs 5.6 months (p = 0.014). A higher IFNG score showed a slight, nonsignificant benefit for PFS, 11.6 vs 5.6 months (p = 0.076). Patients with a low TIDE score had significantly improved overall survival (OS), with a median of 32.5 vs 11.5 months (p = 0.011), and notably, it identified all long-term survivors. Similarly, increased IFNG score was significantly associated with improved OS, with a median survival of 23.7 vs 8.8 months (p = 0.01). Conclusions: Immunological gene signatures IFNG and TIDE in pre-treatment tumors are associated with response and outcome for patients with metastatic UM treated with IHP and hold promise as predictive biomarkers, warranting further validation.