Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients

Abstract

Invasive ovarian cancer is associated with poor outcome. The presence of infiltrating regulatory T-cells (Tregs) suppresses protective anti-tumor immune responses, and their accumulation into the tumor microenvironment correlates with reduced survival in ovarian cancer patients. Here, we conducted a detailed characterization of CD4(+) T-cells, CD8(+) T-cells and Treg subsets in the peripheral blood and malignant ascites fluid from seventeen patients with ovarian carcinoma of epithelial origin. Cell distribution, activation status and proliferation status were assessed by multi-color flow cytometry. In ascites fluid, a significant accumulation of CD8(+) cytotoxic T-cells and Tregs was observed compared to peripheral blood. Furthermore, a skewing toward the CD45RA(-) effector/memory compartment was observed in all T-cell subsets in the ascites fluid, but was most pronounced in the Treg population. Regulatory T-cells in the malignant ascites were more activated and had a higher proliferation rate compared to blood-derived cells from the same patient, and their number in ascites was positively correlated with the number of epithelial cells in effusion. In summary, we demonstrate an accumulation of activated CD4(+), CD8(+) and regulatory T-cells in the cancer microenvironment of ovarian carcinoma.

Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

“…Similar to our results, Landskron et al [14] showed the accumulation of T-regs in ascites from EOC patients, which positively correlated with the contents of EpCAM + cells in ascites. They also confirmed proliferation and recruitment of T-regs towards ascites by the expression of CCR4 and Ki-67, and activation by the expression of CD147 and CTLA4 [14]. The T-regs observed in our ascites samples were CD4 + CD25 + CD127 − cells, which is a phenotype consistent with activated T-regs, since in T-regs the CD127 molecule inversely correlates with FoxP3, a well-known marker for activation of immune cells [51,52,53,54].…”

“…T-regs are known to counteract inflammation by controlling immune cells and enabling maintenance of tissue homeostasis [41]. Similar to our results, Landskron et al [14] showed the accumulation of T-regs in ascites from EOC patients, which positively correlated with the contents of EpCAM + cells in ascites. They also confirmed proliferation and recruitment of T-regs towards ascites by the expression of CCR4 and Ki-67, and activation by the expression of CD147 and CTLA4 [14].…”

“…This question is especially important in response to recent reports by Landskron et al [14], who demonstrated that activated regulatory and memory T cells accumulate in malignant ascites. Thus, the lymphocytes profile in ascites assembles elements from an ongoing immunological response against the tumor, together with the generation of a suppressive microenvironment, but is currently poorly understood.…”

Metabolomic characterization of experimental ovarian cancer ascitic fluid

“…We cannot exclude a potential contribution of the two mouse strains in the differences observed in vivo , since the OVCAR3 human cells were grown in immunocompromised mice, while the mouse ID8 cells were grown in C57BL/6 mice with a functioning immune system. Inflammation and the immune system are known to play a critical role in ascites formation (Robinson-Smith et al 2007) and MA contains cytokines and immune cells (Landskron et al 2015). …”

Synthetic biology in cell-based cancer immunotherapy

“…For example, tumors can deplete the microenvironment of tryptophan [7] while also expressing factors to promote regulatory T cell development [81] and effector T cell death [82]. Antibody drugs such as ipilimumab (anti-CTLA-4) and pembrolizumab (anti-PD-1) attempt to address the challenges presented by the microenvironment by blocking inhibitory or apoptotic signals in T cells.…”