Chemoradiotherapy‐induced increase in Th17 cell frequency in cervical cancer patients is associated with therapy resistance and early relapse

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 posttherapeutic 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 pre-therapeutic 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.

Immune landscape of vulvar cancer patients treated with surgery and adjuvant radiotherapy revealed restricted T cell functionality and increased IL‐17 expression associated with cancer relapse

“…In line with previous studies describing Th17 cells as long living effector cells with high proliferative capacity and apoptosis‐resistant phenotype toward different cell death inducers, such as the chemotherapeutic drug cisplatin, 19 Fas‐mediated cell death in murine Th17 cells 34 or chemoradiotherapy in cervical cancer patients, 21 monitoring of vulvar cancer patients during therapy from this study revealed a decrease in CD4 + T cells in the patients' blood, but a significant increase in Th17 frequencies and absolute numbers after aRT in comparison to patients treated with surgery alone. Besides Th17 cells, frequencies of Tc17 cells but not γδT17 cells were also increased after aRT while frequencies of Th2 and Tregs were comparable to the surgery cohort.…”

Alterations in Peripheral Lymphocyte Subsets under Immunochemotherapy in Stage IV SCLC Patients: Th17 Cells as Potential Early Predictive Biomarker for Response

“…Th17 cells are a subset of CD4+ T cells, secrete different cytokines, and play a role in chronic inflammation, autoimmune diseases like Multiple Sclerosis, and cancer [35,36]. Concerning cancer, there are data showing that Th17 cells can promote tumorigenesis and progression depending on the tumor entity [37][38][39]. Th17 cells can contribute to angiogenesis and tumor vascularization [40].…”

“…Theobald et al reported that chemoradiotherapy increased Th17 cells in the peripheral blood of cervical cancer patients and that higher Th17 cells after therapy were associated with recurrent cervical cancer [39].…”

Th17 cells target the metabolic miR-142-5p-SDHC/SDHD axis promoting invasiveness and progression of cervical cancers

“…The constitution of the HPV-associated tumor microenvironment is critical for tumor development, therapy responses and affects progression of disease (5,6). Invasive cervical cancers are often associated with strong inflammatory infiltrates in the stroma (7).…”

“…Th17 cells represent an IL-17-expressing subgroup of Th cells (12). They increase in the blood of cervical cancer patients (13), infiltrate cervical cancer tissues (11) and exhibit pro-inflammatory as well as tumor-promoting properties in different cancer types (6,14,15). During cervical carcinogenesis, we previously demonstrated that cervical cancer cells actively contributed to the infiltration (11) and expansion (10) of Th17 cells in tumor tissues and their presence in situ correlated with advanced tumor stage, lymph node metastases (10,11), reduced responsiveness of patients toward CRT (6) and retrospectively, with cervical cancer recurrence (6,10).…”