Baseline Values of Circulating IL-6 and TGF-β Might Identify Patients with HNSCC Who Do Not Benefit from Nivolumab Treatment

SIMPLE SUMMARY: Immunotherapy has positively modified the natural history of head and neck cancer (HNC), however, adequate biomarkers to identify resistant patients have not yet been identified. We analyzed 18 circulating Th1, antitumor, and Th2, protumor, cytokines in patients with relapsed/metastatic HNC treated with the immune checkpoint inhibitor nivolumab. Blood samples were collected at baseline (T0) and after 3 cycles of nivolumab (T1). Data extracted at T0 have been related to survival; the comparison between T0 and T1 explored the effect of immunotherapy. Elevated IL-6 and TGF-β values at T0 identified patients with poor survival. Increases of CCL-4, IL-15, IL-2 and CXCL-10, all Th1 cytokines, occurred between T0 and T1 but did not correlate with survival. We suggest that circulating cytokines may represent a tool to identify patients resistant to immunotherapy. The increase of circulating Th1 cytokines during treatment with nivolumab suggests that the drug modulates the tumor microenvironment. However, the lack of correlation between these changes and survival highlights that immunosuppressive mechanisms can prevail. This finding supports the combination of immune checkpoint inhibitors with agents that inhibit other immunosuppressive pathways. ABSTRACT: Background: The immunotherapy of head and neck cancer induces a limited rate of long-term survivors at the cost of treating many patients exposed to toxicity without benefit, regardless of PD-L1 expression. The identification of better biomarkers is warranted. We analyzed a panel of cytokines, chemokines and growth factors, hereinafter all referred to as ‘cytokines’, as potential biomarkers in patients with head and neck cancer treated with nivolumab. Materials and methods: A total of 18 circulating cytokines were analyzed. Samples were gathered at baseline (T0) and after 3 courses of nivolumab (T1) in patients with relapsed/metastatic disease. The data extracted at T0 were linked to survival; the comparison of T0–T1 explored the effect of immunotherapy. Results: A total of 22 patients were accrued: 64% current heavy smokers, 36% female and 14% had PS = 2. At T0, ROC analysis showed that IL-6, IL-8, IL-10 and TGF-β were higher in patients with poor survival. Cox analysis demonstrated that only patients with the IL-6 and TGF-β discriminate had good or poor survival, respectively. Longitudinal increments of CCL-4, IL-15, IL-2 and CXCL-10 were observed in all patients during nivolumab treatment. Conclusion: In this small population with poor clinical characteristics, this study highlights the prognostic role of IL-6 and TGF-β. Nivolumab treatment is associated with a positive modulation of some Th1 cytokines, but it does not correlate with the outcome.