T Cell Costimulatory and Inhibitory Receptors as Therapeutic Targets for Inducing Anti-Tumor Immunity

Abstract

Central to the normal function of the immune system is its ability to distinguish between self and non-self since failure to do so could provoke the onset of autoimmune disease. To avoid this possibility, the immune system employs several processes that include, negative selection, peripheral tolerance, and limiting DC antigen priming of naïve T cells to the lymph nodes. Naïve T cells must receive two independent signals from these antigen-presenting cells (APC) that other cells cannot provide if they are to become productively activated. The first is antigen-specific and occurs when T cell antigen receptors encounter the appropriate antigen-MHC complex on the APC--Signal 1. A second, antigen-independent signal is delivered through a T cell costimulatory molecule that engages its APC-expressed ligands--Signal 2. In the absence of a costimulatory signal T cells typically enter a state of anergy. Furthermore, the extent to which T cell activation occurs can be held in check through specific inhibitory receptors expressed on T cells. Understanding the basic mechanisms of how T cell activation is regulated has led to the development of therapeutic approaches for targeting T cell costimulatory and inhibitory pathways for turning on, or preventing the turning off immune responses in subjects with cancer. In this review we will discuss several T cell costimulatory and inhibitory pathways known to influence the development of anti-tumor immunity and how experimental manipulation of these signaling pathways has led to the generation of protective, or curative anti-tumor immunity in mice and humans.

Preferential killing of cancer cells and activated human T cells using ZnO nanoparticles

“…Signal transduction through the TCR pathway is recognized as an essential event required for resting T cells to enter the cell cycle and proliferate [22]. A second signal provided by ligation through the CD28 receptor protein augments TCR signaling and enables maximal T cell activation and proliferation [22]. Thus, our findings revealing a spectrum of toxicity profiles that correlate with the activation status and proliferative capacity of the cell supports the hypothesis that ZnO NP preferentially target rapidly dividing cells.…”

“…This hypothesis is further supported by studies comparing responses in healthy primary resting T cells to identical cultures in which cells were either activated through the T cell receptor signaling pathway or via both TCR and CD28 costimulation pathways (figure 1). Signal transduction through the TCR pathway is recognized as an essential event required for resting T cells to enter the cell cycle and proliferate [22]. A second signal provided by ligation through the CD28 receptor protein augments TCR signaling and enables maximal T cell activation and proliferation [22].…”

Stimulation of Human CD4+ T Lymphocytes via TLR3, TLR5 and TLR7/8 Up-Regulates Expression of Costimulatory and Modulates Proliferation

“…PD-1 is expressed by B cells, T lymphocytes (activated but not resting), and myeloid cells, in contrast to the more restricted expression of CD28 and CD152. PD-1 is also expressed in the thymus primarily on CD4 – CD8 – T cells, during this transition from double negative to double positive [17]. B7-H1 binds its receptor PD-1 along with another ligand, B7-DC.…”

Co‐culture of Head and Neck Squamous Cell Carcinoma Spheroids with Autologous Monocytes Predicts Prognosis

“…Cells of the MNP, e.g. present antigens to B-and T lymphocytes as well as co-regulate lymphocytes via direct interaction of CD80 ⁄ 86 to CD28 on lymphocytes [3]. Furthermore, these cells secrete cytokines and other substances, e.g.…”