In the past decade, checkpoint inhibitors, such as PD-1 antibody and PD-L1 antibody, have made a significant impact on cancer treatment, marking a shift in the paradigm of how certain cancers are approached and managed. These drugs are part of a class known as immunotherapy, which works by harnessing the body's immune system ( particularly T cells for PD-1 antibody and PD-L1 antibody drugs) to fight cancer.
The 2018 Nobel Prize in Physiology or Medicine was awarded to Tasuku Honjo and James Allison for their discoveries in cancer immunology. Professor Honjo was awarded due to his discovery of the programmed death molecule-1 (PD-1) on T cells. Professor Allison discovered another important immunosuppressive molecule: cytotoxic T-lymphocyte antigen-4 (CTLA-4).
T cell activation is a crucial process in the immune response, enabling the body to target and eliminate pathogens such as viruses and bacteria, as well as cancer cells. This process is intricate and tightly regulated, requiring several signals to ensure that T cells are activated only when truly needed, to avoid damaging normal, healthy cells. T cell activation is fundamental to both the adaptive immune response, enabling the body to remember and respond more efficiently to pathogens it has encountered before, and to the efficacy of certain immunotherapies in treating diseases like cancer.
Here’s a simplified overview of how T cell activation works:
Initial Recognition and Signal 1
Antigen Presentation: The process begins when an antigen-presenting cell (APC), such as a dendritic cell, macrophage, or B cell, processes a foreign antigen (a specific part of a pathogen or cancer cell) and presents it on its surface bound to a major histocompatibility complex (MHC) molecule.
T Cell Receptor (TCR) Engagement: A T cell with a receptor (TCR) specific to that antigen-MHC complex recognizes and binds to the complex. This specificity means that each T cell can only bind to a particular antigen, allowing the immune system to target specific threats.
Full Activation and Signal 2
Co-stimulatory Signals: For full activation, T cells also require a second signal, which typically comes from the interaction between co-stimulatory molecules on the APC (such as CD80 or CD86) and their receptors on the T cell (such as CD28). This requirement acts as a safeguard to prevent accidental activation.
Cytokine Secretion: Once the T cell receives both the antigen-specific signal and the co-stimulatory signal, it becomes fully activated. Activated APCs also release cytokines, which further stimulate T cell proliferation and differentiation.
Proliferation and Differentiation: The activated T cell begins to proliferate (clone itself) and differentiate into various types of effector T cells tailored to the specific immune response needed. For example, CD8+ T cells can become cytotoxic T lymphocytes (CTLs) that kill infected or cancerous cells, whereas CD4+ T cells can differentiate into helper T cells (Th cells) that support other immune cells through cytokine secretion.
Regulation and Checkpoints
Immune checkpoints are regulatory pathways integral to the immune system’s ability to modulate the extent of an immune response, preventing autoimmunity and controlling tissue damage. Proteins such as CTLA-4 and PD-1 are part of these checkpoints and can inhibit T cell activation and function, acting as a "brake" on the immune response. Since cancer cells exploit these pathways to avoid immune detection, checkpoint inhibitors such as PD-1 antibody and PD-L1 antibody have been developed as a means to unleash an immune response against cancer.
TCR / pMHC interaction (signal 1), CD28 co-stimulation (signal 2), and PD1 (checkpoint) (Figure 2 from Nikolaos Patsoukis et al., Revisiting the PD-1 pathway. 2020 Sci. Adv. DOI:10.1126/sciadv.abd2712)
