Circulating immunosuppression correlates with worse clinical outcome in head and neck cancer patients undergoing immunotherapy treatment

Head and neck squamous cell carcinoma (HNSCC) represents one of the most aggressive and heterogeneous groups of human neoplasms. Despite the introduction of immunotherapy, only a limited number of patients obtained long-term benefits. If it is well known that the immunosuppressive tumor microenvironment plays a pivotal role in sustaining tumor growth, the role of circulating immunosuppressive cells remains unclear. In this study we evaluated the impact of Tregulatory subsets (Treg), myeloid-derived suppressor cells (LOX-1⁺PMN-MDSC and M-MDSC) and soluble immune checkpoints (sICs) in recurrent/metastatic (R/M) HNSCC patients undergoing pembrolizumab treatment as first line therapy. Peripheral blood mononuclear cells derived from 40 (R/M) HNSCC patients were analysed at baseline by cytofluorimetry. Results showed that responder patients have significantly low levels of circulating LOX-1⁺PMN-MDSC (p=0.021). Moreover, patients with low levels of LOX-1⁺PMNMDSC (<0.33%) and CD137⁺Treg cells (<0.081%) have prolonged survival (LOX-1⁺PMNMDSC: PFS p=0.004; OS: p=0.009; CD137⁺Treg: PFS p=0.02; OS: p=0.01). The percentage of CD137⁺Treg cells results also positively correlated with performance status (p=0.0004). Multivariate analysis showed that LOX-1⁺PMN-MDSC is an independent prognostic factor of PFS (HR:5.65 95% p=0.009) and OS (HR:5.45 95% p=0.01). Concurrently, evaluation of sICs in the serum of these patients by Luminex assay showed that IDO appears to be the major player of circulating immunosuppression molecules, with a significant impact on OS (p=0.01) and PFS (p=0.02). Our results suggest that in R/M HNSCC patients the levels of CD137+Treg, Lox1-MDSC and IDO impact on immunotherapy treatment and could be used as biomarkers to select patients improving the efficacy of therapies.