An immune checkpoint is a molecular pathway that regulates the activity of the immune system. In cancer biology, the term usually refers to inhibitory interactions between cell-surface proteins that restrain immune responses, particularly those of T cells. These pathways normally help prevent damage to healthy tissues, but cancers can exploit them to escape immune attack. Drugs called immune checkpoint inhibitors interrupt selected inhibitory interactions, allowing immune cells to respond more effectively against some tumors. A checkpoint is therefore a biological regulatory mechanism, not the drug used to block it. (cancer.gov)
Biological role
T-cell activation depends on several interacting signals. Recognition of an antigen presented by the major histocompatibility complex provides specificity, while costimulatory signals help determine whether a productive response develops. Inhibitory checkpoint pathways counterbalance activating signals rather than simply switching the entire immune system off. The outcome depends on the receptors and partner molecules present, their location, and the state of the responding cells. (nobelprize.org)
Checkpoint regulation contributes to peripheral immune tolerance, which limits responses against the body’s own tissues. Its importance is illustrated by experiments in which loss of checkpoint molecules produces excessive immune activation or autoimmunity. Checkpoints operate both within responding T cells and through interactions with other cells; CTLA-4, for example, can reduce the availability of activating molecules on neighboring antigen-presenting cells. These mechanisms distinguish checkpoint regulation from a general absence of immune competence. (nobelprize.org)
Major checkpoint pathways
CTLA-4
CTLA-4, or cytotoxic T-lymphocyte-associated protein 4, is an inhibitory receptor expressed by activated T cells and regulatory T cells. It shares the ligands CD80 and CD86 with the activating receptor CD28. These ligands are displayed by antigen-presenting cells. CTLA-4 limits their availability for CD28-mediated stimulation, thereby restraining T-cell activation. (nobelprize.org)
One experimentally demonstrated mechanism is trans-endocytosis: a CTLA-4-expressing cell captures CD80 or CD86 from another cell and internalizes it for degradation. This reduces the other cell’s ability to deliver costimulation. CTLA-4 therefore can regulate immune responses through effects on surrounding cells, not solely through signals inside the T cell bearing the receptor. (pubmed.ncbi.nlm.nih.gov)
PD-1 and its ligands
PD-1, or programmed cell death protein 1, is another inhibitory receptor. Its ligands include PD-L1 and PD-L2. These molecules occur on immune cells and other cell types; some tumors express substantial amounts of PD-L1. Engagement of PD-1 suppresses activating signals and can limit the ability of T cells to attack a tumor. (nobelprize.org)
Research using biochemical reconstitution and intact cells identified CD28 as a major target of PD-1-mediated inhibition. This finding connects the inhibitory PD-1 pathway directly to the control of costimulation. PD-1 also participates in the regulation of persistently stimulated T cells, including cells affected by T-cell exhaustion. CTLA-4 and PD-1 have distinct but overlapping functions; their activities are not confined exclusively to separate anatomical locations. (pmc.ncbi.nlm.nih.gov)
LAG-3
LAG-3, or lymphocyte activation gene 3 protein, is an additional inhibitory checkpoint receptor targeted in cancer treatment. Relatlimab blocks LAG-3, whereas nivolumab blocks PD-1. On March 18, 2022, the US Food and Drug Administration approved their fixed-dose combination for adults and children aged 12 years or older with unresectable or metastatic melanoma. This extended approved checkpoint blockade beyond the CTLA-4 and PD-1/PD-L1 pathways. (fda.gov)
Checkpoint blockade in cancer
Immune checkpoint inhibitors are a form of cancer immunotherapy, commonly using monoclonal antibodies to interfere with a receptor or its ligand. Their principal purpose is to modify immune regulation rather than directly poison cancer cells. Blocking PD-1 or PD-L1, for example, can prevent an inhibitory interaction that otherwise restrains tumor-directed T cells. (cancer.gov)
Checkpoint inhibitors are used in selected settings across several cancers, including melanoma, lung cancer, kidney cancer, bladder cancer, and Hodgkin lymphoma. Their effectiveness is not uniform across cancer types or patients. Some responses are prolonged, while other tumors do not respond or subsequently progress. Combining blockade of different checkpoints can improve outcomes in particular settings, but can also increase immune-related toxicity. (cancer.gov)
Biomarkers and limitations
A biomarker is a measurable characteristic that provides information about a disease or its likely response to treatment. Biomarkers relevant to checkpoint therapy include tumor PD-L1 expression, mismatch repair deficiency, and tumor mutational burden. These describe different aspects of tumor biology and are not interchangeable tests. (cancer.gov)
No single marker guarantees a response. PD-L1-negative tumors can sometimes respond, while tumors with mismatch repair deficiency or numerous mutations may still resist treatment. Response reflects interactions among tumor characteristics, immune cells, and the surrounding tissue environment. Biomarkers consequently provide context-dependent information rather than a universal classification of tumors as responsive or unresponsive. (nobelprize.org)
Immune-related adverse effects
Removing inhibitory control can also produce immune attacks on healthy tissues. Checkpoint therapy can cause inflammation affecting the skin, intestines, liver, lungs, hormone-producing glands, and other organs. These immune-related adverse effects differ from the typical toxicities of treatments that directly damage rapidly dividing cells. Their frequency and severity vary with the drug and treatment regimen, and some can be life-threatening. (cancer.gov)
Historical development
CTLA-4 was cloned in 1987, and PD-1 was identified in 1992. In 1996, James P. Allison and colleagues demonstrated that CTLA-4 blockade could promote rejection of established tumors in mice. Subsequent research established the inhibitory function of PD-1 and the therapeutic potential of blocking its pathway. Allison and Tasuku Honjo received the 2018 Nobel Prize in Physiology or Medicine for discoveries underlying cancer therapy through inhibition of negative immune regulation. (nobelprize.org)