Cancer Immunotherapy: The Role Regulatory T Cells Play and What Can be Done to Overcome their Inhibitory Effects

Abstract

Since multiple lines of experimental and clinical data clearly identified regulatory T cells as an integral part of the immune response, these cells have become a major focus of investigation in tumor immunology. Regulatory T cells are in place to dampen ongoing immune responses and to prevent autoimmunity, but they also have profound effects in blocking therapeutic anti-tumor activity. Therefore regulatory T cells are seen as a major hurdle that must be overcome in order for cancer immunotherapy to reach its therapeutic potential. Regulatory T cells are heterogeneous with sub-populations that exhibit distinct functional features. Here we will review the individual sub-populations in regards to their mode of action and their potential impact on blocking anti-tumor immunity. Approaches to measure function and frequency of regulatory T cells in model systems and clinical trails will be discussed. Finally, we will describe possible ways to interfere with regulatory T cell-mediated immune suppression with the focus on recent pre-clinical and clinical findings.

B cells inhibit the antitumor immunity against an established murine fibrosarcoma

“…The MCC was induced in male BALB/c mice by the subcutaneous implantation of a methylcholanthrene pellet and was maintained by syngeneic transplantation. MCC is an immunogenic murine tumor characterized by an initial immunogenic state (tumor volume, 100-400 mm 3 ) followed by a tolerance state (tumor volume, >500 mm B-cell depletion. The B cell-depleting monoclonal mouse anti-CD20 antibody (clone, 18B12), kindly provided by Biogen Idec (Cambridge, MA, USA), or rat non B cell-depleting immunoglobulin G (IgG) antibody (catalog.…”

“…4B). When CI was evaluated in B cell-depleted mice bearing large tumors (>500 mm 3 ), an increased rate of tumor rejection (80%) was observed in depleted mice, whereas no rejection was observed in the control IgG-treated group (Chi-square test; P=0.00026). This result reinforces the possibility that B cells may be interfering with T cell activity.…”

“…The mechanisms responsible for antitumor immunity failure in individuals with cancer include a wide diversity of soluble immunosuppressive factors, including transforming growth factor β (TGFβ), interleukin 10 (IL-10), reactive oxygen species (ROS), enzymes and inhibitory ligands such as Fas ligand (FasL) or TNF-related apoptosis-inducing ligand, released by tumor cells or by other regulatory cells in the tumor microenvironment (2). The majority of immunotherapies against cancer aim to counteract the action of regulatory cells in order to achieve tumor remission or prevent recurrences; of these, T regulatory cells (Tregs) have been the major focus of efforts to therapeutically modulate their inhibitory activity (3,4 …”

“…Methylcolanthrene-induced murine fibrosarcoma (MCC) is a highly immunogenic tumor that elicits an early specific antitumor immune reaction, which is not strong enough to impede tumor growth (18)(19)(20)(21). The antitumor response declines at a certain tumor volume (~500 mm 3 ) and disappears comprising a state of tolerance (18)(19)(20)(21). Immunological characteristics of MCC and its rapid growth in vivo make it a suitable model to study mechanisms underlying tumor immunity and tumor-induced immunosuppression.…”

Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model

“…However, it has been noted that tumors take advantage of Tregs to help them evade immune attacks. Increased numbers of Tregs were found in peripheral blood and especially in tumor microenvironments of patients with malignancies (16)(17)(18). It is likely that Tregs contribute to decreasing immunity during tumor development and progression, leading to poor outcomes in cancer patients.…”