Abstract
Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post‐therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer.
Highlights
Peripheral blood samples obtained from 70 cervical cancer patients, treated from 2017 to 2020 in the Saarland University Hospital, and 70 healthy female age-matched controls (HC) were used for monitoring of the percentages of CD4+IL17+ (Th17) cells. 35 patients were treated with surgery alone, and 35 patients received chemoradiotherapy (n = 20 adjuvant chemoradiotherapy and n = 15 primary chemoradiotherapy)
When we investigated Th17 cells, we found that pretherapeutic frequencies of Th17 cells in the patients‘ blood of the analyzed cohorts correlated with advanced tumors based on Federation of Gynecology and Obstetrics (FIGO) stages (Fig. S1A; r = 0.4386, P = 0.0005)
Our study identified a novel role of Th17 cells in cervical cancer therapy
Summary
Cervical cancer is a consequence of persistent infection with high-risk human papillomaviruses (HPV) and the fourth most frequent cancer in women worldwide.Standard of care therapy for patients with cervical cancers is a stage-dependent therapy according to the International Federation of Gynecology and Obstetrics (FIGO) classification, which includes besides surgery alone in early stages, adjuvant platinum-basedAbbreviations (C/EBPb), CAAT/enhancer-binding protein b; aCRT, adjuvant chemoradiotherapy; EGFR, epidermal growth factor receptor; FIGO, International Federation of Gynecology and Obstetrics; HPV, human papillomavirus; IL, interleukin; MAPK, mitogen-activated protein kinase; MDSCs, myeloid-derived suppressor cells; OSM, oncostatin M; pCRT, primary chemoradiotherapy; PMA, phorbol-12-myristate-13-acetate; qRT-PCR, quantitative real-time polymerase chain reaction; STAT3, signal transducer and activator of transcription; Th1, T-helper(Th)-1 cells; Th17, T-helper(Th)-17 cells; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.Molecular Oncology 15 (2021) 3559–3577 a 2021 The Authors. Standard of care therapy for patients with cervical cancers is a stage-dependent therapy according to the International Federation of Gynecology and Obstetrics (FIGO) classification, which includes besides surgery alone in early stages, adjuvant platinum-based. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies Different T-cell subsets react in a differential way to therapeutic approaches showing enhanced sensitivity or survival [4,5,6,7] This may result in a therapy-induced micromilieu in the patients‘ blood and tumor tissues, which may affect progression and clinical outcome of the disease
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