Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression

Abstract

Surgery is the primary therapeutic strategy for most solid tumours; however, modern oncology has established that neoplasms are frequently systemic diseases. Being however a local treatment, the mechanisms through which surgery plays its systemic role remain unknown. We have investigated the influence of cytoreduction on the immune system of primary and recurrent ovarian cancer. All ovarian cancer patients show an increase in CD4+ CD25+ FOXP3+ circulating cells (CD4 T(reg) ). CD4/CD8 ratio is increased in primary tumours, but not in recurrent neoplasms. Primary cytoreduction is able to increase circulating CD4 and CD8 effector cells and decrease CD4 naïve T cells. CD4+ T(reg) cells rapidly decreased after primary tumour debulking, while CD8+ CD25+ FOXP3+ (CD8 T(reg) ) cells are not detectable in peripheral blood. Similar results on CD4 T(reg) were observed with chemical debulking in women subjected to neoadjuvant chemotherapy. CD4 and CD8 T(reg) cells are both present in neoplastic tissue. Interleukin (IL)-10 serum levels decrease after surgery, while no changes are observed in transforming growth factor-β₁ and IL-6 levels. Surgically induced reduction of the immunosuppressive environment results in an increased capacity of CD8+ T cells to respond to the recall antigens. None of these changes was observed in patients previously subjected to chemotherapy or affected by recurrent disease. In conclusion, we demonstrate in ovarian cancer that primary debulking is associated with a reduction of circulating T(reg) and an increase in CD8 T-cell function. Debulking plays a beneficial systemic effect by reverting immunosuppression and restoring immunological fitness.