Mitigating SOX2-potentiated Immune Escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing Nanosatellite Vaccine

Clin Cancer Res. 2018 Sep 1;24(17):4242-4255. doi: 10.1158/1078-0432.CCR-17-2807. Epub 2018 May 16.


Purpose: The response rates of Head and Neck Squamous Cell Carcinoma (HNSCC) to checkpoint blockade are below 20%. We aim to develop a mechanism-based vaccine to prevent HNSCC immune escape.Experimental Design: We performed RNA-Seq of sensitive and resistant HNSCC cells to discover central pathways promoting resistance to immune killing. Using biochemistry, animal models, HNSCC microarray, and immune cell deconvolution, we assessed the role of SOX2 in inhibiting STING-type I interferon (IFN-I) signaling-mediated antitumor immunity. To bypass SOX2-potentiated STING suppression, we engineered a novel tumor antigen-targeted nanosatellite vehicle to enhance the efficacy of STING agonist and sensitize SOX2-expressing HNSCC to checkpoint blockade.Results: The DNA-sensing defense response is the most suppressed pathway in immune-resistant HNSCC cells. We identified SOX2 as a novel inhibitor of STING. SOX2 facilitates autophagy-dependent degradation of STING and inhibits IFN-I signaling. SOX2 potentiates an immunosuppressive microenvironment and promotes HNSCC growth in vivo in an IFN-I-dependent fashion. Our unique nanosatellite vehicle significantly enhances the efficacy of STING agonist. We show that the E6/E7-targeted nanosatellite vaccine expands the tumor-specific CD8+ T cells by over 12-fold in the tumor microenvironment and reduces tumor burden. A combination of nanosatellite vaccine with anti-PD-L1 significantly expands tumor-specific CTLs and limits the populations expressing markers for exhaustion, resulting in more effective tumor control and improved survival.Conclusions: SOX2 dampens the immunogenicity of HNSCC by targeting the STING pathway for degradation. The nanosatellite vaccine offers a novel and effective approach to enhance the adjuvant potential of STING agonist and break cancer tolerance to immunotherapy. Clin Cancer Res; 24(17); 4242-55. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / immunology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / pharmacology
  • Drug Resistance, Neoplasm / immunology
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immune Tolerance
  • Immunotherapy
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Mice
  • Nanostructures / administration & dosage
  • Nanostructures / chemistry
  • SOXB1 Transcription Factors / genetics*
  • SOXB1 Transcription Factors / immunology
  • Squamous Cell Carcinoma of Head and Neck / immunology*
  • Squamous Cell Carcinoma of Head and Neck / prevention & control
  • Squamous Cell Carcinoma of Head and Neck / therapy
  • Tumor Microenvironment / immunology


  • B7-H1 Antigen
  • CD274 protein, human
  • Cancer Vaccines
  • Interferon Type I
  • Membrane Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • STING1 protein, human