Targeting Costimulatory Molecules to Improve Antitumor Immunity

Abstract

The full activation of T cells necessitates the concomitant activation of two signals, the engagement of T-cell receptor by peptide/major histocompatibility complex II and an additional signal delivered by costimulatory molecules. The best characterized costimulatory molecules belong to B7/CD28 and TNF/TNFR families and play crucial roles in the modulation of immune response and improvement of antitumor immunity. Unfortunately, tumors often generate an immunosuppressive microenvironment, where T-cell response is attenuated by the lack of costimulatory molecules on the surface of cancer cells. Thus, targeting costimulatory pathways represent an attractive therapeutic strategy to enhance the antitumor immunity in several human cancers. Here, latest therapeutic approaches targeting costimulatory molecules will be described.

Costimulation of Effector CD8+ T Cells: Which Receptor is Optimal for Immunotherapy?

“…Specifically, recent work completed has shown that compared to CD28 stimulation, NKG2D stimulation in human and murine effector CD8 + T cells decreased the expression and secretion of anti-inflammatory cytokines IL-10, IL-9, IL-13 through activation of the β-catenin pathway [11]. Additionally, + T cells that also play a critical role in shaping T cell function, including the NKG2D, OX-40, and 4-1BB receptors [3,4]. Once a T cell has been activated, it is recruited to the site of infection or tumor where it performs effector functions to destroy the target cells.…”

“…Each of these receptors ultimately promotes effector T cell proliferation, survival, and cytokine production, as well as the generation and maintenance of memory T cells. However, each receptor seems to induce these functions to a different degree causing a unique activation status [3,4,11]. It is likely that the differential signaling of these receptors changes the gene-expression profiles and effector functions in T cells, but the details of these mechanismsare still not clear.…”

“…However, at an infection or tumor site activated T cells will likely be stimulated through these receptors and the resulting changes in gene expression will alter their effector functions. CD28, NKG2D, OX-40, and 4-1BB are all expressed on activated CD8 + T cells [3,4]. The ligands for these receptors are also likely expressed on cells present at the effector site.…”

“…The ligands for these receptors are also likely expressed on cells present at the effector site. The expression of ligands for CD28 and 4-1BB is restricted to activated professional APCs, such as dendritic cells, macrophages, and B cells, while the ligand for OX-40 can be induced on professional APCs as well as on T cells, Langerhans cells, mast cells, NK cells, endothelial cells, and smooth muscle cells [3,4]. Many of these cells that express the ligands are present at the infection or tumor site, thus these receptors are likely stimulated during effector responses.…”

Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

“…During the last few decades, many efforts have been made to create safe and effective tumor Immunotherapy strategies with the objective of tumor eradication (Rosenberg., 2001;Aguilar et al, 2011;Danylesko et al, 2012), including immune-activating antibodies, co-stimulation, tumor antigen vaccines and modified cancer cells are generally aimed to inducing CTL responses against tumor cells (Qiu et al, 2009). T lymphocytes represent a crucial component of the antitumor immunity; Ag-induced antitumor T cells activation and proliferation are regulated by both positive and negative co-stimulatory molecules (Phan et al, 2003;Capece et al, 2012). Although there are several potential mechanisms that could contribute to the resistance of solid tumors to host immunity surveillance, a major consideration is the engagement of negative regulatory receptors on activated T cells by ligands expressed in the tumor microenvironment (Blank et al, 2004;Topfer et al, 2011).…”