Targeting STAT3 Signaling Reduces Immunosuppressive Myeloid Cells in HNSCC

Objectives: Head and neck squamous cell carcinoma (HNSCC) affects 600,000 new patients each year and accounts for over 90% of head and neck cancer cases. As a point of convergence for many oncogenic signaling pathways, cumulative evidence suggests that constitutively activated signal transducer and activator of transcription (STAT3) may contribute to sustaining immunosuppressive status. The effect of STAT3 on immature myeloid cells (IMC) related immunosuppressive status has still not been well investigated in HNSCC.
Methods: Human tissue microarray was used to detect the expression of p-STAT3 and IMC, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and immature dendritic cells (iDC), related markers. Pearson correlation analysis and hierarchal clustering analysis were used to explore the relation between p-STAT3 and IMC related markers. Immunocompetent spontaneous HNSCC (Tgfbr1/Pten 2cKO) mice model was performed to detect the antitumor immunity effect by inhibiting of p-STAT3. In addition, we developed a new biomimetic Nano-platform drug delivery system for possible future application of STAT3 inhibitors in HNSCC.
Results: In the present study, we observed that high levels phosphorylated of STAT3 are significantly associated with the markers for both MDSCs and TAMs in HNSCC. Additionally, we showed that targeting STAT3 signaling with a tolerable selective inhibitor S3I-201 significantly decreased IMC such as MDSCs, TAMs and iDCs in genetically defined mice HNSCC model. In addition, the new biomimetic Nano-platform may be a promising strategy to delivery STAT3 inhibitors to treat HNSCC.
Conclusions: These findings highlight that targeting STAT3 signaling may be effective to enhance antitumor immunity via immunosuppressive myeloid cells in HNSCC.