Th17 cells favor migration and invasiveness of cervical cancer cells under hypoxia in an IGF2BP2-dependent manner

Abstract

Hypoxic regions of cervical cancers mediate suppression of the human papillomavirus (HPV) oncoproteins E6 and E7 in an AKT-dependent manner causing oxygen-dependent reversible growth arrest of cancer cells. Furthermore, numbers of T-helper (Th)-17 cells increase during cervical carcinogenesis in cancer tissues, Th17 differentiation is favored by hypoxia and their presence is linked with AKT-dependent therapy resistance, metastases and relapse. As both factors, hypoxia and Th17 cells, are associated with poor prognosis of patients, potential synergistic mechanisms between both are not described so far. In this study, we showed that Th17 cells enhance the expression of hypoxia-related glycolytic enzymes and transporters and functionally favor increased glucose uptake, proliferation and migration of 2D cultures of hypoxic cervical cancer cells as well as invasion of 3D spheroids. As the responsible mediator of increased proliferation, migration and invasion, we identified the RNA-binding protein IGF2BP2 by using small interfering RNAs (siRNAs) for IGF2BP2 as well as small molecule IGF2BP2 inhibitors of the benzamidobenzoic acid class. Consistently, Th17 numbers in cervical cancer biopsies correlated with IGF2BP2 expression associated with lymph node metastases and relapse. Correspondingly, a combination of IGF2BP2 expression and Th17 cell numbers >10/mm2 in situ was associated with reduced recurrence-free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote tumor progression under hypoxic conditions and suggest evaluation of Th17 cells as well as IGF2BP2 as potential target for therapeutic approaches in cervical cancer.