Intercepting the evolution of pro-tumoral myeloid cells during the initiation of oral cancer

The National Institute of Dental and Craniofacial Research awarded the Regents of the University of Michigan $275,574 on January 1, 2029, under the Oral Diseases and Disorders Research program (CFDA 93.121) to investigate the evolution of pro-tumoral myeloid cells during the initiation of oral cancer in HPV-negative head and neck squamous cell carcinomas.

The project develops a preclinical mouse model to study the transition from oral epithelial dysplasia to HNSCC, focusing on SOX2-driven malignant transformation. Researchers will conduct high-dimensional immune landscape analysis to characterize a unique myeloid cell phenotype that suppresses anti-tumor immune response. The work employs a multipronged approach to investigate how myeloid cells in SOX2-positive lesions develop suppressive phenotypes and will test pharmacological and genetic strategies to intercept this evolution. The project will generate a high-resolution atlas of functionally distinct myeloid cell subsets in precancerous lesions and identify key intervention points for therapeutic development.

Place of performance is Ann Arbor, Michigan. The period of performance runs through August 31, 2028.

Abstract

Earlier detection and treatment of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (hnscc) has the greatest potential to improve overall survival rates, which have remained stagnant at around 50% for several decades. Patients with HPV-negative hnscc often have a clinical history of oral epithelial dysplasia (OED), but IT remains unclear which lesions will progress to cancer. Through comprehensive sequencing of these tumors, IT is known that a common (about 20%) genetic alteration event is the amplification at locus 3Q26.3, which harbors oncogene SOX2 (SRY-box transcription factor 2). Previous research revealed that SOX2 inhibits a critical immune sensing pathway by degrading stimulator of interferon genes (sting) protein in hnscc cancer cells. The activation of the sting pathway is essential for establishing a spontaneous anti-tumor immune response, as IT promotes the presentation of tumor antigens on the surface of myeloid cells, leading to the activation of cancer-killing t cells. IT remains unclear how sting signaling in tumor-resident immune cells may be impacted during SOX2-driven malignant transformation. To investigate this, we have developed a preclinical mouse model to study the transition from OED to hnscc. Upon high-dimensional analysis of the immune landscape, we find a unique myeloid cell phenotype that suppresses anti-tumor immune response. This study will utilize a multipronged approach to investigate the mechanism by which myeloid cells in SOX2-positive lesions develop terminal suppressive phenotypes. We will test pharmacological and genetic strategies to intercept the evolution of these pro-tumoral myeloid cells. Ultimately, this project will provide a high- resolution atlas of functionally distinct myeloid cell subsets in precancerous lesions and identify key interception points for therapeutic intervention.