Xevinapant plus chemoradiotherapy negatively sculpts the tumour immune microenvironment in head and neck cancer

Xevinapant is an orally bioavailable antagonist of select members of the inhibitor of apoptosis protein (IAP) family. Despite promising initial data, combining xevinapant with chemoradiation (CRT) failed to improve outcomes in the TrilynX phase III trial for locally-advanced head and neck squamous cell cancer (SCCHN). We investigated the addition of xevinapant to CRT in immunocompetent mouse models of SCCHN and found maintained or improved locoregional control in vivo in a CD8+ T-cell-independent manner. In mEER, numbers of tumour-infiltrating cytotoxic CD8+ T-cells and NK cells were reduced, with remaining CD8+ T-cells characterised by PD-1hi CD38hi expression and Nr4a3 dynamics consistent with non-responsiveness to antigenic re-stimulation. Furthermore, xevinapant plus CRT significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute phase proteins and decreased levels of necroptosis mediator RIPK3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumour-immune microenvironment which may explain its lack of clinical benefit. Overall design: RNA-seq profiling of 8- to 14-week-old females C57BL/6 WT mice, inoculated with head and neck cancer cells from two cell lines and treated with vehicle, radiotherapy and chemoradiotherapy with or without combination with Xevinapant (5 mice per treatment group). Two models of murine immunocompetent HPV-negative and HPV-positive head and neck cancer were used, MOC1 and mEER, respectively.