Modulation of Tumor Immunity by Soluble and Membrane-Bound Molecules at the Immunological Synapse

Abstract

To circumvent pathology caused by infectious microbes and tumor growth, the host immune system must constantly clear harmful microorganisms and potentially malignant transformed cells. This task is accomplished in part by T-cells, which can directly kill infected or tumorigenic cells. A crucial event determining the recognition and elimination of detrimental cells is antigen recognition by the T cell receptor (TCR) expressed on the surface of T cells. Upon binding of the TCR to cognate peptide-MHC complexes presented on the surface of antigen presenting cells (APCs), a specialized supramolecular structure known as the immunological synapse (IS) assembles at the T cell-APC interface. Such a structure involves massive redistribution of membrane proteins, including TCR/pMHC complexes, modulatory receptor pairs, and adhesion molecules. Furthermore, assembly of the immunological synapse leads to intracellular events that modulate and define the magnitude and characteristics of the T cell response. Here, we discuss recent literature on the regulation and assembly of IS and the mechanisms evolved by tumors to modulate its function to escape T cell cytotoxicity, as well as novel strategies targeting the IS for therapy.

Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

“…(70) The lack of CAR blockade by serum protein may be explained by the avidity of CAR T cells for membranous target antigen, which may be increased by interactions between adhesion molecules and other accessory molecules present on the surface of the T-cell and tumor cells. (71)…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…Tregs secrete granzymes (serine proteases) and perforin to impair the function of effector T-cells (i.e., Th cells and CTLs) and NK cells, as well as immunosuppressive factors such as IL-10 or TGFβ [ 104 ]. They also express CD25 (a component of the IL-2 receptor) at their cell surface, and due to their high avidity for IL-2 create a sink for this T-cell growth factor [ 105 ].…”

Modulation of Host Immunity by the Human Metapneumovirus

“…On their cell surface, mature DCs increase the density of MHC-I and MHC-II, B7 receptors (CD80 and CD86), and other molecules needed for efficient communication with T cells, such as CD40 and chemokine receptors needed for trafficking into secondary lymphoid tissues (201)(202)(203). Furthermore, mature DCs secrete cytokines with the capacity to skew the commitment of T cells toward phenotypes contingent on the threat sensed, including interleukins and transforming growth factor ␤1 (TGF-␤1) (204). MHCs, B7 receptors, and cytokines are key signals provided to T cells synaptically engaged with activated DCs, which are commonly referred to as signals 1, 2, and 3, respectively (204).…”

“…Furthermore, mature DCs secrete cytokines with the capacity to skew the commitment of T cells toward phenotypes contingent on the threat sensed, including interleukins and transforming growth factor ␤1 (TGF-␤1) (204). MHCs, B7 receptors, and cytokines are key signals provided to T cells synaptically engaged with activated DCs, which are commonly referred to as signals 1, 2, and 3, respectively (204). The intensities of these signals, particularly signals 1 and 2 (205), determine the outcome of T cell stimulation toward anergy (unresponsive phenotype), tolerance (regulatory phenotype), or immunity (effector phenotype).…”