Characterization of the Immune Response to PD-1 Blockade during Chemoradiotherapy for Head and Neck Squamous Cell Carcinoma.

Abstract

Simple SummaryBlockade of the PD-1/L1 interaction represents a breakthrough in the treatment for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Clinical and translational research suggests that this interaction may play a role in immune evasion during chemoradiotherapy. Using an immune-competent murine model of HNSCC, we demonstrate improved efficacy of PD-1 blockade with concurrent cisplatin-based chemoradiotherapy. Taking this approach into a clinical trial evaluating the anti-PD-1 agent, pembrolizumab, combined with chemoradiotherapy in HNSCC, we characterized the peripheral blood immune response to therapy. Our findings highlight that this combination is active in the murine model and circulating PD-1+ T-cell proportions were decreased during the clinical trial. However, additional findings from the clinical trial suggest a shift towards expression of other markers of immune exhaustion. As this treatment approach is being explored in large, randomized trials, these findings provide insight into potential pathways for treatment failure.Background: Chemoradiotherapy is a standard treatment for HNSCC. Blockade of the PD-1/L1-2 interaction may represent a target to overcome immune escape during this treatment. Methods: Utilizing a HNSCC mEERL C57BL/6 mouse model, we evaluated a PD-1 blockade alone or in combination with cisplatin-based chemoradiotherapy. Next, we evaluated peripheral blood mononuclear cells (PBMCs) with relative PD-1, TIM-3, and LAG-3 expression, and myeloid-derived suppressor-like (MDSC-like) populations from a clinical trial evaluating PD-1 blockade with chemoradiotherapy in HNSCC. Finally, we analyzed the effect of therapy on human T-cell clonality through T-cell Receptor (TCR) sequencing. Results: Anti-PD-1 monotherapy induced no response in the mEERL model; however, combination with chemoradiotherapy improved tumor clearance and survival. PBMCs from patients treated with this combination therapy demonstrate a decline in circulating T-cell populations with knockdown of PD-1 expressing CD3+CD4+ and CD3+CD8+ T cells during treatment. However, TIM-3, LAG-3 expressing T-cell and MDSC-like populations concordantly rose. During treatment, the TCR repertoire demonstrates overall clonal expansion, with both unique and previously reported T-cell clones. Conclusions: Our murine HNSCC model demonstrates efficacy of PD-1 blockade during chemoradiotherapy. However, while PD-1-expressing T cells decreased with this therapy, human PBMC findings also identified an increase in populations contributing to immune exhaustion. These findings further characterize PD-1 blockade during chemoradiotherapy for HNSCC and highlight potential competing mechanisms of immune evasion.