TGF- mRNA levels in circulating extracellular vesicles are associated with response to anti-PD1 treatment in metastatic melanoma

Introduction: Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed. Methods: This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs; the RNA levels of PD-L1, IFN-gamma, and TGF-beta were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients. Results: Patients with high TGF-beta expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs. 1.8 months; p = 0.006) and overall survival (17.9 vs. 2.63 months; p = 0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-beta expression at baseline had smaller lesions (2.41 +/- 3.27 mL vs. 42.79 +/- 101.08 mL, p < 0.001) and higher dissimilarity (12.01 +/- 28.23 vs. 5.65 +/- 8.4; p = 0.018). Discussion: These results provide evidence that high TGF-beta expression in EVs is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.