While many advancements have been made in the treatment of cancerous tumor cells, the unique properties and physiological characteristics of tumor cells continue to pose unique challenges to researchers. Characteristics ranging from abnormal blood vasculature to increased interstitial fluid pressure to a general absence of lymphatics in solid tumors, present distinctive challenges and prime opportunities for more innovative and targeted therapies.
Effective eradication of tumor cells is a challenging task for the immune system. The complex process involves multiple cellular components which must work together harmoniously to achieve an appropriate inflammatory response. In their normal state, immune cells are designed to ensure that they are not constitutively active which may lead to other serious conditions or diseases. Upon binding of ligand to its corresponding receptors, down-regulation or suppression of T cells is promulgated through a variety of markers located on both antigen-presenting cells and tumor cells.
A primary focus of researchers today is to identify mechanisms that avoid the binding of T cells to ligands that promote tolerance induction. In this manner, T cells would be more readily positioned to fight cancerous tumors. These aforementioned markers are known as immune checkpoint receptors. Among the most commonly identified immune checkpoint receptor-ligand combinations include Tim-3/Galectin 9, LAG-3/MHCII, CTLA-4/CD80, CD86, PD-L1/PD-1.
Programmed Cell Death Protein-1 (PD-1)
One immune checkpoint protein that has recently been shown to be especially effective is PD-1 (Programmed Cell Death Protein-1). Specifically, immune checkpoints are proteins that act as T cell receptor (TCR) signaling partners that deliver either positive or negative signals to T lymphocytes.
Under normal conditions, these proteins are critical for self-tolerance, but in tumors, these immune checkpoint proteins can allow the tumor to evade the antitumor immune response. Blocking the actions of these proteins can produce a potent antitumor response.
The PD-1 protein is a negative costimulatory receptor that can bind two different but related ligands, PD-L1 and PD-L2. Upon binding to either of these ligands, signals generated by PD-1 inhibit the activation of the immune response in the absence of “danger signals” such as LPS or other molecules associated with bacteria or other pathogens.
Immune checkpoint inhibitors play an important role in treating tumors and immune checkpoints have emerged as popular immunotherapy targets, that inhibit regulatory pathways in the immune system.
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