Differentiated Thyroid Cancer Is Associated With Sex-specific Immune Response

Background Thyroid cancer (TC) exhibits sex-based disparities in incidence, progression, and outcomes, with women of reproductive age exhibiting more favorable prognoses than men. This study investigates sex differences in immune cell dynamics within peripheral blood and the tumor microenvironment (TME) in TC. Methods We performed a prospective study of 27 patients (16 females/11 males) undergoing thyroidectomy for TC or high-risk thyroid nodules. Tissue and blood were collected for immune cell analysis using flow cytometry and spatial transcriptomics. Differential-expression of immune-related genes was assessed with DESeq2, and immune cell frequencies were compared between sexes. Results Males showed higher frequencies of dividing natural killer (NK) cells (9.67 vs 1.29, P < .001) and T-cell immunoreceptor with Ig and ITIM domains (Tigit) + CD8 T cells (2.34 vs 0.87, P = .04) in the TME. In contrast, females tended to have higher frequencies of mature NK (2.5 vs 1.08, P = .07) and CD8 T-cells (0.95 vs 0.68, P = .09). Spatial transcriptomics revealed that men had reduced expression of HLA-DRB (P = .001, antigen presentation) in both surrounding normal tissue and the tumor border and a trend for increased LAG3 (P = .09) in normal tissue compared to women. In the core of the tumor, we observed increased IFNAR1 (P = .04), CD68 (P = .04), and B2M (P = .02) in men vs women. Conclusion Our study reveals significant sex-based differences in immune cell composition and gene expression within the TME of TC. Males exhibit a more immunosuppressive profile, with higher levels of inhibitory immune markers and lower frequencies of functional NK cells. Our findings highlight the importance of incorporating sex-specific immune profiles into development of targeted therapies for advanced TC.