Age- and Sex-Related Immune Dysfunction in the Tumor Microenvironment Shortens Survival in Anaplastic Thyroid Cancer

Jocelynn Gianna Colunga Minutti, BA (Advisor: Roza Nurieva, PhD)

          Anaplastic thyroid cancer (ATC) accounts for half of all thyroid cancer-related deaths. Unlike other subtypes, women do not have a higher incidence, and the average patient age is 65 years old. Extensive immunoprofiling of the tumor microenvironment (TME) using single-cell RNA sequencing (sc-RNA-seq) has recently shown that, while immunosuppressive, ATC exhibits a higher immune infiltration than papillary thyroid cancer (PTC). This could be a therapeutic advantage for immunotherapy treatments. Male ATC patients have more aggressive growth; however, no further research has gone into sexual dimorphism. This thesis aims to elucidate on it using a preclinical murine model of ATC in C57BL/6 mice. We found sexual dimorphism in tumor growth and TME composition in young mice using orthotopic and subcutaneous models. The female TME had significantly higher anti-tumor immune infiltrations (B cells, CD8+ T cells and N1 neutrophils), while males had a higher T cell exhaustion, T regulatory cells (Tregs), and M2 macrophages. Sexual dimorphism reduced with age, as seen in our subcutaneous aged ATC mouse cohort (60w). The TME in this group was immunosuppressive with a higher myeloid composition. Cell depletions revealed that CD8+ T and macrophages were the main players in females and males respectively. Lastly, we determined a possible role of microbiome in sexual dimorphism by doing an FMT engraftment with the opposite sex.

Advisory Committee:

• Roza Nurieva, PhD, Chair
• Anastasios Maniakas, MD, PhD
• Seyed Moghaddam, MD
• Alexandre Reuben, PhD
• Pamela Wenzel, PhD

Join via Zoom (Please contact Ms. Colunga Minutti for her Zoom meeting info.)