Transcriptome signatures of treatment responses in a preoperative window of opportunity trial of nivolumab and tadalafil in resectable squamous cell carcinoma of the head and neck

Abstract

Abstract Background Immunotherapy with nivolumab, an anti-PD-1 blocking antibody, is clinically approved for the management of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) but it benefits only a minority of patients. The phosphodiesterase (PDE) 5 inhibitor tadalafil was found to lower intratumoral myeloid-derived suppressor cells and regulatory T cells in SCCHN patients. Here we describe exploratory analyses of immune-related gene expression correlates of nivolumab with or without concurrent administration of tadalafil administered for 4 weeks before planned surgical resection in the context of a completed randomized, window-of-opportunity trial. Methods RNA-seq was performed on pre- and post-treatment tumor tissues from 28 patients receiving either nivolumab alone (n\xa0=\xa012) or nivolumab and tadalafil (n\xa0=\xa016). RNA was sequenced (NextSeq 500) using 75bp paired-end chemistry at a depth of ∼50 million reads. Results Consistent with previous work, pretreatment biopsies of HPV(+) SCCHN (n\xa0=\xa019) were more strongly immune infiltrated when compared to HPV(-) (n\xa0=\xa09) cancers. Preliminary principal component analysis of pretreatment gene expression suggests that select transcripts related to T cells and inflammation were predicitve of clinical outcomes in HPV(+) SCCHN. Nivolumab treatment enhanced expression of a broad range of immune-related genes in both HPV(+) and HPV(-) SCCHNs and this signature was amplified by tadalafil. Whereas transcript patterns consistent with enhanced myeloid cell infiltration after treatment were observed in both, HPV(+) and HPV(-) HNSCCs, T cell gene expression signatures were more pronounced in HPV(+) cancers. Conclusions These results point to diverse intratumoral immune states triggered by nivolumab/tadalafil in HPV(+) when compared to HPV(-) SCCHNs. They challenge the notion that increased presence of intratumoral T lymphocytes alone is associated with favorable therapeutic responses to PD1 inhibition in SCCHN. Yet, select pretreatment transcripts associated with innate and/or adaptive immune responses may have prognostic relevance. Clinical trial identification NCT 03238365. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb. Disclosure All authors have declared no conflicts of interest.