PD-1 (Programmed Cell Death Protein 1)

PD-1 was first cloned in 1992 by Tasuku Honjo and colleagues at Kyoto University, who identified it as a gene upregulated during programmed cell death in T cells, hence the name. The protein is a type I transmembrane glycoprotein of the immunoglobulin superfamily, containing an extracellular N-terminal domain, a transmembrane region, and a cytoplasmic tail with two tyrosine-based motifs: an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). The ITSM is essential for PD-1's inhibitory function, recruiting the phosphatase SHP-2 upon ligand binding. PD-1 is expressed on activated T cells, B cells, and myeloid cells, and its expression is induced by T-cell receptor signaling and cytokines such as IL-2 and IL-7. The gene PDCD1 is located on chromosome 2q37.3 in humans.

PD-1 exerts its inhibitory effects primarily by binding to its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). PD-L1 is constitutively expressed on many tissues and is upregulated on tumor cells and antigen-presenting cells in response to inflammatory cytokines, particularly interferon-gamma. When PD-1 engages PD-L1, the ITIM and ITSM motifs become phosphorylated, recruiting SHP-2, which dephosphorylates key signaling molecules in the T-cell receptor pathway, including ZAP70 and PI3K. This leads to reduced T-cell proliferation, cytokine production, and cytotoxic activity, and promotes T-cell exhaustion. PD-1 also affects T-cell metabolism, shifting cells away from glycolysis and promoting fatty acid oxidation. The interaction is a key mechanism of peripheral tolerance, preventing excessive immune responses and autoimmunity.

Many cancers exploit the PD-1/PD-L1 axis to evade immune surveillance. Tumor cells upregulate PD-L1, which engages PD-1 on tumor-infiltrating lymphocytes, effectively turning off anti-tumor immunity. This discovery led to the development of immune checkpoint inhibitors that block PD-1 or PD-L1, thereby reactivating T cells. The first PD-1 inhibitor, pembrolizumab (Keytruda), was approved by the FDA in 2014 for metastatic melanoma, followed by nivolumab (Opdivo) later that year. These drugs have since been approved for dozens of cancer types, including non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, and many others. Combination therapies with CTLA-4 inhibitors, chemotherapy, or targeted agents have further improved outcomes. However, response rates vary, and many patients develop resistance, prompting research into biomarkers such as PD-L1 expression, tumor mutational burden, and microsatellite instability.

Beyond oncology, PD-1 is implicated in chronic viral infections, where persistent antigen exposure leads to T-cell exhaustion, a state partially driven by PD-1 upregulation. Blocking PD-1 has been explored as a therapeutic strategy for HIV, hepatitis B, and hepatitis C, though results have been mixed. PD-1 also plays a role in autoimmune diseases; genetic polymorphisms in PDCD1 are associated with susceptibility to systemic lupus erythematosus and type 1 diabetes. In the clinic, PD-1 inhibitors can cause immune-related adverse events (irAEs), such as colitis, pneumonitis, and endocrinopathies, due to unleashed autoimmunity. A notable edge case is the phenomenon of hyperprogression, where a minority of patients experience accelerated tumor growth after checkpoint inhibitor therapy, possibly linked to MDM2 amplification or EGFR alterations. Additionally, PD-1 expression on regulatory T cells (Tregs) complicates the picture, as PD-1 blockade may enhance Treg activity in some contexts, potentially limiting efficacy.

Immune checkpoint

A regulatory pathway in the immune system that maintains self-tolerance and modulates immune responses; PD-1 is a key inhibitory checkpoint.

T-cell exhaustion

A state of T-cell dysfunction characterized by progressive loss of effector function, often driven by chronic antigen exposure and PD-1 upregulation.

Ligand

A molecule that binds to a receptor; PD-L1 and PD-L2 are ligands for PD-1.

Monoclonal antibody

An antibody produced by a single clone of cells, designed to bind a specific target; PD-1 inhibitors are monoclonal antibodies.

Immune-related adverse events (irAEs)

Side effects of immune checkpoint inhibitors that result from enhanced immune activity against normal tissues.