In Situ Pro-Inflammatory Effects of Dazostinag Alone or With Chemotherapy Upon the Tumor Microenvironment of Patients With Head and Neck Squamous Cell Carcinoma.

Abstract

Purpose: The tumor microenvironment (TME) is difficult to model in an in vivo cancer research setting. This study leveraged intratumor microdosing using CIVO with spatial profiling to evaluate the effects of the STING agonist dazostinag alone or with chemotherapy on cellular responses within the native TME of intact human tumors.

Patients and methods: This phase 0 study enrolled adult patients with head and neck squamous cell carcinoma (HNSCC) planned for surgical intervention. Intratumoral microdose injections of dazostinag (maximum dose: 1.68 µg in 0.05 mg/mL solution) alone or combined with various chemotherapies were delivered via CIVO to tumors 24-, 48-, 72-, or 96- hours prior to resection. Each tumor sample was prepared for analysis using immunohistochemistry and in situ hybridization. Analysis of the microdosed tumors using GeoMx Digital Spatial Profiler and CosMx Spatial Molecular Imager was performed in one patient.

Results: Type 1 interferon signaling was induced with dazostinag alone and combined with chemotherapy from multiple cell types within the TME, including immune cells. Dazostinag also shifted polarization of macrophages from an immune-suppressive to a pro-inflammatory phenotype at 24 hours post-injection. Enrichment of cytotoxic T-cells was observed in regions of localized dazostinag exposure, coinciding with increased chemokine (CXCL9) expression. Based on Cleaved Caspase 3, an apoptosis marker, dazostinag plus chemotherapy increased cellular apoptosis relative to either drug alone.

Conclusions: Utilizing CIVO and spatial profiling technology, dazostinag alone and combined with chemotherapy promoted an early pro-inflammatory response and enhanced chemotherapy-mediated cell death in the native TME of intact human HNSCC tumors.