Soluble immune biomarkers to predict clinical outcome in head and neck patients treated with immunotherapy

Background Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive and immunosuppressive tumor. Immune checkpoint inhibitors (ICIs), especially antiprogrammed death-ligand 1 (PD-1) antibodies, have emerged as first-line treatment for recurrent/metastatic (R/M)HNSCC patients. Despite the introduction of immunotherapy, the overall response rate remains low, highlighting the urgent need for reliable predictive biomarkers to guide treatment decisions. Soluble immune checkpoints (sICs), circulating proteins derived from alternative splicing of membrane proteins, seem to modulate the immune response to tumor cells, influence cancer development, prognosis and treatment. Aim In this study we evaluated the concentrations of sICs (CD137, CTLA-4, PD-1, PD-L1, PDL2, TIM3, LAG3, GITR, HVEM, BTLA, IDO, CD80, CD27, CD28) in (R/M)HNSCC patients, before the beginning of immunotherapy, to identify potential novel biomarkers of treatment response and survival. Methods Serum samples from 40 patients with (R/M) HNSCC treated with pembrolizumab as first line were analyzed, at baseline, for the levels of 14 sICs by Luminex assay. These parameters were correlated with response to therapy, overall survival (OS), progressionfree survival (PFS) and performance status (PS). Results Results showed that high baseline levels of sIDO (>88.87pg/ml) and sLAG3 (>152.8pg/ml) are associated with poor prognosis, both in terms of PFS (p=0.04 and p=0.01, respectively) and OS (p=0.04 and p=0.02, respectively). Furthermore, a significative correlation between different sICs and PS was observed: patient with PS=2 had high levels of sIDO, sPD1, sLAG3, sCD28 and sCD137 compared to patients with PS=0 (p<0.05). Finally, using a multivariate analysis, sIDO emerged as an independent prognostic factor of OS (p=0.02), suggesting its crucial role among circulating immunosuppressive molecules. Conclusions Our results indicate that in (R/M)HNSCC patients the evaluation of sICs could help to define an immune profile able to predict clinical outcome, and in particular sIDO and sLAG3 revealed as predictive biomarkers of anticancer treatment success in this patient’s setting.