The human immune system consists of two arms: innate immunity and adaptive immunity. Innate immunity is characterized as quick, non-specific, with no memory. Innate immune cell types include tissue macrophages, monocytes, dendritic cells (DC), eosinophils, basophils, and neutrophils.
Adaptive immunity, by contrast, is slower in response but with high specificity and generates memory. Adaptive immune cell types are made up of T cells and B cells. T cells can be further categorized as helper T cells, cytotoxic T cells (CTL, also called killer T cells), and T regulatory cells, among additional sub-types. B cells, upon activation, differentiate into plasma cells to produce antibodies. Plasma cells are dubbed as "antibody factories."
A key component of the adaptive immune response arm is the elimination of unwanted cells by CTLs. "Unwanted" cells can be infected body cells as well as cancer cells. CTLs carry out this mission by releasing a pair of enzymes, perforin and granzymes. Perforin, as the name indicates, pokes holes on the surface membrane of cells destined for destruction by CTL. Granzyme B, is too large in size to enter cells, but with perforin "paving the way," is now ready for target cell entry, triggering the activation of the apoptotic pathway to bring unwanted cells for destruction.
In cancer cells, this very activity by CTLs is blocked by a number of mechanisms, including PD-1 activation. PD-1 (programmed cell death 1), is expressed as CTL cell-surface receptors. PD-1 is a negative regulator of CTL. Specifically, upon activation, PD-1 signals CTLs to go into "dormancy" without immune response. Cancer cells secrete an abundant amount of PD-L1, the ligand that binds to and activates PD-1, leading to CTL inactivity, allowing cancer cells to evade immune attack. Two FDA-approved drugs, nivolumab (trade name Opdivo) and pembrolizumab (trade name Keytruda), respectively, are designed to block PD-1, the negative CTL regulator, thereby promoting CTL activation and boosting immune response against malignant cells. These drugs have been reported to demonstrate efficacy in the treatment of several cancer types, including melanoma, Hodgkin lymphoma, and non small-cell lung cancer (NSCLC).
