Immunotherapy and microbiota interventions as potential treatment options for anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy that accounts for approximately 50% of all thyroid cancer-related deaths despite its low incidence. While it is known that thyroid cancer has a higher incidence in women and a worse prognosis in men, age itself is an independent negative prognostic factor. Despite the median patient age for ATC being 65 years, no animal studies have accounted for age in this type of cancer, which represents a vital gap that must be addressed. Therefore, this research aims to investigate the impact of age and sex on ATC outcomes and treatment response. A Kaplan-Meier survival analysis demonstrated that younger female ATC patients had better survival odds than young males. However, aged patients had poorer overall survival, regardless of sex, suggesting that aging changes the biological mechanisms that confer better survival in younger females. Like ATC patients, our murine ATC model shows that young males display accelerated ATC growth compared to females, while older mice have similarly high growth rates regardless of sex. We correlated worse ATC outcomes in young male mice and aged mice with similar immunosuppressive tumor microenvironments (TMEs) that highly express immune co-inhibitory checkpoint molecules such as PD-1, PD-L1, TIM-3, LAG-3, and CTLA-4. In fact, ATC mice positively respond to combinatorial immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) regardless of sex or age, when given early in tumor development. In addition, we found that young mice of opposite sexes have very distinct gut microbial communities at baseline compared to aged mice, and this difference is associated with tumor growth outcomes. Moreover, targeting the microbiota through fecal microbial transplant (FMT) resulted in an antitumor benefit for aged groups disregard of sex. Together, these results reveal sex- and age-related immune mechanisms driving ATC progression and highlight the potential for immunotherapy and microbiota interventions.