Inflammatory signature and restriction of adaptive immunity are associated with unfavorable outcomes on immune checkpoint blockade in patients with advanced head and neck squamous cell carcinoma

BackgroundIn most patients with relapsed or metastatic head and neck squamous cell carcinoma (rmHNSCC), immunotherapy with PD-1 targeting antibodies does not yield durable responses. PD-L1 tissue expression - the most commonly assessed marker for checkpoint inhibiting antibodies - is an insufficient predictor of treatment outcome. MethodsWe evaluated various blood and tissue-based biomarkers in the context of immune checkpoint blockade-based treatment to find suitable response biomarkers in a clinical trial cohort of patients with rmHNSCC. ResultsThe PD-L1 expression level in tumor or tumor microenvironment was not associated with treatment benefit. In contrast, inflammation-related markers such as IL-6, high peripheral neutrophils and high levels of cell-free DNA, as well as markers related to adaptive immune dysfunction such as altered T cell dynamics and secretion of immune checkpoint molecules, were associated with poor clinical outcomes. Patients lacking these high-risk markers performed remarkably well on inhibition of immune checkpoints with pembrolizumab. ConclusionsBiomarker-guided patient selection for pembrolizumab monotherapy or novel combinatorial approaches - potentially including anti-inflammatory agents - for patients with immune-impaired, inflammatory profiles may be the next step in personalizing immunotherapy for these hard-to-treat patients.