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

For 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. Vulvar cancer is a rare gynecologic tumor treated with radiotherapy that affects the host immune system. Here, we provide new insight into systemic therapy-induced individual immunity of patients, revealing increased frequencies of tumor-promoting interleukin(IL)-17-producing CD4+ and CD8+ T cell subsets after radiotherapy, while other T cell subsets important for cancer cell elimination, like T-helper (Th)1 and cytotoxic T cells, were decreased and showed high expression of the Programmed Cell Death Protein (PD) 1 indicating restricted functionality. Moreover, this imbalance within the post-therapeutic immune milieu was associated with shorter recurrence free survival suggesting IL-17 and PD-1 as target for immunotherapy in vulvar cancers.image