Investigator
Saarland University
PD-L1+ CD49f+ CD133+ Circulating tumor cells predict outcome of patients with vulvar or cervical cancer after radio- and chemoradiotherapy
Abstract Background Monitoring individual therapy responses of patients with cancer represents a major clinical challenge providing the basis to early identify metastases and cancer relapse. We previously demonstrated that radio- or chemoradiotherapy affects the systemic cellular milieu of patients with vulvar or cervical cancer and creates individual post-therapeutic environments associated with cancer relapse. Circulating tumor cells (CTCs) in the systemic milieu are related to metastases and relapse; however, their quantitative and phenotypic characteristics during therapy of patients with vulvar and cervical cancer are still unknown. Methods In this prospective, longitudinal study, we verified the presence of CTCs via immunofluorescence and systemically characterized CTCs by flow cytometry from the blood of 40 patients with vulvar and 115 patients with cervical cancer receiving surgery, adjuvant radiotherapy (aRT), chemoradiotherapy (aCRT) or primary chemoradiotherapy (pCRT) and linked the presence of different CTC subpopulations with individual outcome of disease. Results Pre-therapeutic cytokeratin+ CD45− CTC numbers significantly correlated with tumor FIGO stages, lymph node metastases and relapse. While surgery only did not significantly alter CTC occurrence, aRT and aCRT as well as pCRT differentially decreased or increased CTCs in patients with both tumor entities compared to baseline levels. Therapy-mediated increased CTC numbers were directly linked with subsequent cancer recurrence on follow-up. Phenotypic characterization of CTCs revealed enhanced expression of the stem cell marker CD133 as well as the integrin α6 (CD49f) after aRT, aCRT and pCRT. Furthermore, the aRT, aCRT and pCRT cohorts exhibited increased proportions of Programmed Cell Death Protein Ligand (PD-L1) expressing cells among post-therapeutic CTCs. Notably, post-therapeutic PD-L1+ CD49f+ CD133+ numbers ≥ 5/ml in patients with vulvar cancer and ≥ 2/ml in patients with cervical cancer were associated with reduced recurrence-free survival on follow-up. Conclusion Our study unravels individual therapy-induced changes in CTC phenotypic characteristics and occurrence in the patients’ blood and their association with cancer relapse. Our results may help to explain differences in the individual courses of disease of patients with vulvar and cervical cancer and suggest PD-L1, CD49f and CD133 as targets for immunotherapy in vulvar and cervical cancer.
Chemoradiotherapy‐induced increase in Th17 cell frequency in cervical cancer patients is associated with therapy resistance and early relapse
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.
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
AbstractFor vulvar cancers, radiotherapy is targeting cancer cells, but also affects the host immune system. As this may affect treatment outcome, in this prospective study, we characterized the individual T cell immune milieu induced by surgery and adjuvant radio +/− chemotherapy (aRT) systemically in the blood of vulvar cancer patients and found increased frequencies of Interleukin (IL)‐17‐producing CD4+ and CD8+ T cells after aRT while frequencies of Th1 and perforin‐producing CD8+ killer cells were strongly diminished. Phenotypic characterization revealed enhanced expression of the ectonucleotidase CD39 on Th17 and Tc17 cells as well as CD8+ perforin+ cells after aRT. Furthermore, the aRT cohort exhibited increased proportions of Programmed Cell Death Protein (PD‐1) expressing cells among Th1 and CD8+ perforin+ cells, but not among Th17 and Tc17 cells. High post‐therapeutic levels of Th17 and Tc17 cells and low proportions of Th1 and CD8+ perforin+ cells expressing PD‐1 was associated with reduced recurrence free survival on follow‐up. In conclusion, our study defines individual therapy‐induced changes in the cellular immune milieu of patients and their association with cancer relapse. Our results may help to explain differences in the individual courses of disease of vulvar cancer patients and suggest PD‐1 and IL‐17 as targets for immunotherapy in vulvar cancer.
Th17 cells target the metabolic miR ‐142‐5p–succinate dehydrogenase subunit C/D ( SDHC / SDHD ) axis, promoting invasiveness and progression of cervical cancers
During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse; however, the underlying Th17‐driven mechanisms are not fully understood. Here, using microarrays, we found that Th17 cells induced an epithelial‐to‐mesenchymal transition (EMT) phenotype of cervical cancer cells and promoted migration and invasion of 2D cultures and 3D spheroids via induction of microRNA miR‐142‐5p. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR‐142‐5p and provided evidence that Th17–miR‐142‐5p‐dependent reduced expression of SDHC and SDHD mediated enhanced migration and invasion of cancer cells using small interfering RNAs (siRNAs) for SDHC and SDHD, and miR‐142‐5p inhibitors. Consistently, patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patient biopsies correlated with increased numbers of Th17 cells. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4 + T cells > 43.90% in situ was associated with reduced recurrence‐free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.
