Wnt/B-catenin activation and TP53 mutations associate with distinct immune profiles in advanced thyroid cancer

Abstract Context Anaplastic thyroid carcinomas (ATCs) and poorly differentiated thyroid carcinomas (PDTCs) exhibit distinct immune-related gene expression profiles. Most ATCs are characterized by active immune interactions (hot or altered immunosuppressed immunophenotypes), while PDTCs are largely immunologically inert (cold immunophenotypes). Objective This study aimed to elucidate the mechanisms driving these divergent immunological fates, focusing on the Wnt/β-catenin pathway and TP53 mutations. Results Our data reveal that ATCs frequently harbor TP53 mutations (83.3%), which correlate with a hot immunophenotype, characterized by high expression of β-catenin-regulated cytokine CCL4 and recruitment of CD103+ dendritic cells. Conversely, PDTCs, with a lower incidence of TP53 mutations (12.5%), often exhibit a cold immunophenotype. In cold cancers and PDTCs, β-catenin is overexpressed suggesting that Wnt/β-catenin pathway activation drives immune exclusion through CCL4 downregulation. Further analysis indicated that loss of p53 function is inversely correlated with β-catenin expression. P53-mutated cancers showed significantly higher expression of CCL4 and densities of CD103+ dendritic cells compared to their p53-wild-type counterparts. Additionally, p53-mutated ATCs expressed a higher number of immune-related genes, supporting the role of p53 loss in activating immune responses in cancer. Conclusion Our study indicates a potential correlation between the activation of the Wnt/β-catenin pathway and the development of cold thyroid cancers, which may be mediated by the suppression of CCL4 expression. Concurrently, mutations in the p53 gene appear to be linked with the occurrence of hot thyroid cancers. While these associations are compelling, they are based on observational data. Experimental research is necessary to determine the causal relationships underlying these findings.