Targeting Tumor Hypoxia Inhibits Aggressive Phenotype of Dedifferentiated Thyroid Cancer

Abstract

Context: Hypoxia is commonly observed in multiple aggressive cancers. Its role remains unclear in the biology and therapy of dedifferentiated thyroid cancer (DDTC).

Objective: We aimed to elucidate hypoxia's roles in DDTC tumor biology.

Methods: We discovered and confirmed hypoxia's correlation with dedifferentiation status, poor prognoses, and immune checkpoints in thyroid cancer using transcriptome data from our center and Gene Expression Omnibus (GEO) database. Then, the effect of targeting hypoxia was investigated via treating anaplastic thyroid cancer (ATC) cells with acriflavine (ACF) in vitro and in vivo, and hypoxia was analyzed for its association with response to immunotherapy in patients.

Results: Hypoxia score was positively associated with dedifferentiation status, and high hypoxia score significantly correlated with reduced overall survival, TP53 mutation, and elevated expression of immunosuppression-related markers in DDTC. ACF and siRNA targeting HIF-1α significantly suppressed growth and proliferation of thyroid cancer cells in vitro and in vivo, and reduced c-MYC and PDL1 expression in ATC. HIF-1α showed a positive correlation with PDL1 expression in DDTC. Integrated analyses of phosphoproteome and RNA sequencing data revealed that ACF's target was connected with differentiation genes and immune checkpoints via tumor-related kinases in ATC. Furthermore, hypoxia score was associated with immunotherapeutic response in some cancer types.

Conclusion: Hypoxia score serves as a significant indicator for dedifferentiation status, prognoses, and immunotherapeutic response predicted by Tumor Immune Dysfunction and Exclusion in DDTC patients. Targeting hypoxia by ACF is useful to alleviate aggressive phenotype of ATC in a preclinical model of DDTC.

Keywords: DDTC; TME; acriflavine; hypoxia; immunotherapy.