Cure Alveolar Soft Part Sarcoma International (iCureASPS)

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.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303883/

1. Introduction

T-cell activation requires a double signal, as stated in the “two signal theory.” The first signal is provided by the engagement of the T-cell receptor (TCR) by its cognate antigen, through the interaction with the peptide-major-histocompatibility complex (MHC) on antigen presenting cells (APCs). In 1987, Jenkins et al. [1] demonstrated that TCR engagement was not sufficient for a full T-cell activation. Costimulatory molecules expressed on the surface of APCs are responsible for the second signal, known as costimulatory signal. The interactions of costimulatory molecules with cognate receptors on the surface of T cells result in clonal T-cell expansion and differentiation, as well as in carrying out their effector functions [2]. For several costimulatory molecules a bidirectional signaling has been reported, because their signaling pathways are also directed toward APCs. The lack of costimulation results in a nonresponsive state of T cells, known as anergy [3]. Following the initial activation, coinhibitory molecules are induced to dampen the immune response. Complex interactions implicating both overlapping and distinct costimulatory pathways underlie the generation of the immune response; thus, the tightly regulated expression of costimulatory and coinhibitory molecules, both in time and space, is crucial to provide an efficient immune protection avoiding autoimmunity.

Costimulatory molecules belong to two major families: B7/CD28 family and tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) family. All molecules belonging to B7/CD28 family are members of the larger immunoglobulin superfamily and are involved in the triggering of cell-mediate immune response. Instead, the TNF/TNFR family members are involved in the later phases of T-cell activation and are induced from hours to days following the TCR engagement [2].

The presence of an efficient costimulation is crucial for improving antitumor immunity. In fact, one of the mechanisms through which tumors are able to evade immune surveillance is the lower expression of costimulatory molecules or the upregulation of coinhibitory molecules. The lack of costimulation in the tumor microenvironment could be responsible for the generation of anergic T cells and, consequently, the absence of an appropriate antitumor immune response [4].

T-cell activation requires a double signal, as stated in the “two signal theory.” The first signal is provided by the engagement of the T-cell receptor (TCR) by its cognate antigen, through the interaction with the peptide-major-histocompatibility complex (MHC) on antigen presenting cells (APCs). In 1987, Jenkins et al. [1] demonstrated that TCR engagement was not sufficient for a full T-cell activation. Costimulatory molecules expressed on the surface of APCs are responsible for the second signal, known as costimulatory signal.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303883/

Costimulation( cliff notes )

Costimulation

In some immune responses, a B cell or T cell becomes activated when an antigen or nonself cell binds to it. Activation then initiates proliferation. In most immune responses, however, activation requires the presence of a costimulator. Those two signals, an antigen and a costimulator, are required to initiate the immune response, ensuring that healthy self cells are not destroyed. Costimulation may occur in two ways:


-Cytokines, released by helper T cells and APCs, act as costimulators. Cytokines are protein hormones that influence cell growth. When a helper T cell becomes activated or an APC engulfs an antigen, the helper T cell or APC secretes a cytokine called interleukin.

-Helper T cells and APCs act as costimulators. Activated T cells or APCs that display antigens activate B cells or T cells when they temporarily bind to them.

https://www.cliffsnotes.com/study-guide ... timulation