Aptamer-mediated transcriptional gene silencing of Fox p 3 inhibits regulatory T cells and potentiates antitumor response.

The inhibition of immunosuppressive mechanisms may switch the balance between tolerance and surveillance, leading to an increase in antitumor activity. Regulatory T cells play an important role in the control of immunosuppression, exhibiting the unique property of inhibiting T cell proliferation. These cells migrate to tumor sites or may be generated at the tumor site itself from the conversion of lymphocytes exposed to tumor microenvironment signaling. Because of the high similarity between regulatory T cells and other lymphocytes, the available approaches to inhibit this population are nonspecific and may antagonize antitumor response. In this work we explore a new strategy for inhibition of regulatory T cells based on the use of a chimeric aptamer targeting a marker of immune activation harboring a small antisense RNA molecule for transcriptional gene silencing of Fox p 3, which is essential for the control of the immunosuppressive phenotype. The silencing of Fox p 3 inhibits the immunosuppressive phenotype of regulatory T cells and potentiates the effect of the GVAX antitumor vaccine in immunocompetent animals challenged with syngeneic tumors. This novel approach highlights an alternative method to antagonize regulatory T cell function to augment antitumor immune responses.

Boosting Antitumor Response by Costimulatory Strategies Driven to 4-1BB and OX40 T-cell Receptors.

Immunotherapy explores several strategies to enhance the host immune system's ability to detect and eliminate cancer cells. The use of antibodies that block immunological checkpoints, such as anti-programed death 1/programed death 1 ligand and cytotoxic T-lymphocyte-associated protein 4, is widely recognized to generate a long-lasting antitumor immune response in several types of cancer. Evidence indicates that the elimination of tumors by T cells is the key for tumor control. It is well known that costimulatory and coinhibitory pathways are critical regulators in the activation of T cells. Besides blocking checkpoints inhibitors, the agonistic signaling on costimulatory molecules also plays an important role in T-cell activation and antitumor response. Therefore, molecules driven to costimulatory pathways constitute promising targets in cancer therapy. The costimulation of tumor necrosis factor superfamily receptors on lymphocytes surface may transduce signals that control the survival, proliferation, differentiation, and effector functions of these immune cells. Among the members of the tumor necrosis factor receptor superfamily, there are 4-1BB and OX40. Several clinical studies have been carried out targeting these molecules, with agonist monoclonal antibodies, and preclinical studies exploring their ligands and other experimental approaches. In this review, we discuss functional aspects of 4-1BB and OX40 costimulation, as well as the progress of its application in immunotherapies.