Pre-existing systemic immune state and dynamic myeloid remodeling shape response to neoadjuvant PD-L1 blockade.

Neoadjuvant immunotherapy has emerged as a promising strategy for patients with head and neck squamous cell carcinoma. However, the systemic immune mechanisms underlying treatment response remain insufficiently defined. This study evaluated the clinical feasibility and immunological effects of a single neoadjuvant dose of a programmed death-ligand 1 (PD-L1) blocking antibody in patients with resectable head and neck squamous cell carcinoma, with a particular focus on immune cell dynamics. In this phase II, open-label, non-randomized window-of-opportunity study (PIONEER trial, NCT04939480), patients received one dose of the PD-L1-targeting antibody atezolizumab before surgery. Clinical safety, operability, and pathological response were assessed. A translational research program incorporated intensive immune monitoring based on immediate processing of freshly collected peripheral blood samples, enabling reliable quantification of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which are highly sensitive to freeze-thaw procedures. Additional immune profiling was performed to track treatment-induced systemic immune activation and cytokine dynamics. All patients proceeded to surgery without delay, and neoadjuvant atezolizumab was well tolerated. Pathological tumor regression exceeding 50% was observed in 7 of 20 patients (35%), including 5 patients with major pathological response. Treatment induced a transient peak in type II interferon-associated cytokines and defined signatures of cell-mediated immunity approximately 15 days after antibody administration. Patients who achieved robust pathological regression displayed higher baseline frequencies of activated natural killer T cells and exhausted T cells, with further expansion after treatment. Importantly, immediate blood processing revealed that pronounced tumor regression was consistently associated with an early and marked reduction in mature immunosuppressive PMN-MDSC-a finding that would have been obscured by conventional frozen sample workflows. A single neoadjuvant dose of atezolizumab was feasible, safe, and elicited measurable systemic immune activation in patients with resectable head and neck squamous cell carcinoma. Direct analysis of fresh blood uncovered dynamic PMN-MDSC changes as a potential novel pharmacodynamic biomarker of treatment response, emphasizing the advantages of real-time, non-frozen immune cell profiling for complete assessment of immune cell dynamics in neoadjuvant immunotherapy studies. NCT04939480.