Correlations between Alterations of T-Helper 17 Cells and Treatment Efficacy after Concurrent Radiochemotherapy in Locally Advanced Cervical Cancer (Stage IIB–IIIB): A 3-Year Prospective Study

Correlations between Alterations of T-Helper 17 Cells and Treatment Efficacy after Concurrent Radiochemotherapy in Locally Advanced Cervical Cancer (Stage IIB–IIIB): A 3-Year Prospective Study

Introduction

Cervical cancer remains a significant global health issue, particularly in developing countries. In China, the incidence and mortality rates of cervical cancer have been increasing, largely due to the prevalence of high-risk human papillomavirus (HPV) infections and limited access to HPV vaccines. Locally advanced cervical cancer (LACC), classified as International Federation of Gynecology and Obstetrics (FIGO) stages IIB to IIIB, poses a considerable challenge in treatment. Concurrent chemoradiotherapy (cCRT) is the standard treatment for LACC, but the prognosis varies widely, and predictive biomarkers for treatment efficacy are needed.

T-helper 17 (Th17) cells, a subset of CD4+ T cells characterized by the production of interleukin (IL)-17, have been implicated in various cancers, including cervical cancer. Th17 cells are known to promote tumor growth through angiogenesis and inflammation but can also exhibit anti-tumor properties. Despite their dual role, the involvement of Th17 cells in the efficacy of anti-tumor treatments, particularly in cervical cancer, remains poorly understood. This study aimed to investigate the alterations in circulating Th17 cells and related cytokines in LACC patients before and after cCRT and to analyze the correlations between these alterations and treatment efficacy.

Methods

This prospective study enrolled 49 LACC patients (FIGO stages IIB–IIIB) and 23 healthy controls. Patients received a standardized cCRT regimen, including platinum-based chemotherapy, external beam radiotherapy (EBRT), and high-dose-rate brachytherapy. Peripheral blood samples were collected before and after cCRT to measure the percentage of circulating Th17 cells (CD3+CD8–IL-17+ T cells) and related cytokines (IL-17, TGF-β, IL-10, IL-23, IL-6, and IL-22) using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. Treatment efficacy was evaluated based on tumor response, progression-free survival (PFS), and overall survival (OS). Patients were followed up for three years, and statistical analyses were performed to assess correlations between Th17 cell alterations and treatment outcomes.

Results

Treatment Efficacy and Prognosis

Of the 49 patients, 40 completed the cCRT regimen and were included in the final analysis. The overall response rate was 90%, with 82.5% achieving complete remission. The 3-year PFS and OS rates were both 70%. Twelve patients died during the follow-up period, with cancer progression being the leading cause of death.

Variations in Circulating Th17 Cells

The percentage of circulating Th17 cells was significantly higher in LACC patients before cCRT compared to healthy controls (median 4.54% vs. 2.01%, P < 0.001). After cCRT, the percentage of Th17 cells decreased significantly (median 2.89%, P < 0.001) but remained higher than in controls. Patients were divided into two groups based on the degree of Th17 cell reduction: the obviously decreasing (OD) group (n = 27) and the non-obviously decreasing (NOD) group (n = 13). The OD group had a more pronounced decrease in Th17 cells and exhibited better treatment efficacy, longer PFS, and longer OS compared to the NOD group.

Cytokine Levels

Before cCRT, LACC patients had higher levels of IL-6, IL-10, IL-22, and TGF-β and lower levels of IL-23 compared to controls. After cCRT, levels of IL-6, IL-10, IL-17, and IL-23 increased significantly, while TGF-β levels decreased. The OD group had higher IL-10 and IL-17 levels post-cCRT compared to the NOD group, suggesting a stronger immune response in patients with a significant reduction in Th17 cells.

Correlations between Th17 Cells and Cytokines

Positive correlations were observed between Th17 cells and IL-17, IL-22, IL-23, and TGF-β before cCRT. After cCRT, the decrease in Th17 cells was positively correlated with changes in IL-17, IL-22, IL-6, IL-10, and TGF-β levels. These findings indicate that Th17 cells and their associated cytokines play a critical role in the immune response to cCRT in LACC patients.

Discussion

This study provides novel insights into the role of Th17 cells in the treatment of LACC. The findings demonstrate that circulating Th17 cells are elevated in LACC patients and generally decrease after cCRT. However, the degree of reduction varies among patients, and those with a more pronounced decrease in Th17 cells exhibit better treatment outcomes. The study also highlights the complex interplay between Th17 cells and related cytokines, which collectively influence the immune response to cCRT.

The dual role of Th17 cells in cancer—promoting tumor growth while also potentially exerting anti-tumor effects—complicates their involvement in treatment efficacy. In this study, the reduction in Th17 cells post-cCRT was associated with improved outcomes, suggesting that Th17 cells may contribute to tumor progression in LACC. The increase in pro-inflammatory cytokines such as IL-6 and IL-17 after cCRT further supports the role of Th17 cells in mediating the immune response to treatment.

The findings also suggest that variations in Th17 cells and related cytokines could serve as prognostic biomarkers for LACC patients undergoing cCRT. Patients with a significant reduction in Th17 cells and elevated levels of specific cytokines may have a better prognosis, while those with minimal changes may require more aggressive treatment strategies. These results align with previous studies that have identified Th17 cells and cytokines as potential predictors of tumor recurrence and survival in cervical cancer.

Limitations and Future Directions

This study has several limitations, including its single-center design, small sample size, and relatively short follow-up period. The inclusion of patients across a wide range of LACC stages may have introduced variability in the results. Additionally, the study only measured Th17 cells and cytokines at two time points, limiting the ability to capture dynamic changes during treatment.

Future studies should address these limitations by including larger, multicenter cohorts, more frequent sampling during treatment, and longer follow-up periods. Investigating the mechanisms underlying the plasticity of Th17 cells and their interactions with other immune cells could provide further insights into their role in cancer progression and treatment response. Additionally, exploring the potential of targeting Th17 cells and related cytokines as a therapeutic strategy in LACC could improve treatment outcomes.

Conclusion

This 3-year prospective study demonstrates that circulating Th17 cells are elevated in LACC patients and generally decrease after cCRT. A more pronounced reduction in Th17 cells is associated with better treatment efficacy, longer PFS, and longer OS. The study also highlights the complex interplay between Th17 cells and related cytokines, which collectively influence the immune response to cCRT. These findings suggest that variations in Th17 cells and cytokines could serve as prognostic biomarkers for LACC patients, guiding personalized treatment strategies to improve outcomes.

doi.org/10.1097/CM9.0000000000001475

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