The idea that the immune system can fight cancer is not new - but the tools to make it do so effectively have only recently arrived. Understanding the biology behind cancer immunosurveillance helps explain why pembrolizumab works, and why it works better in some patients than others.
How the immune system normally detects threats
The immune system continuously patrols the body for abnormal cells. T cells - a type of white blood cell - are particularly important in this process. They recognise cells that display abnormal proteins (antigens) on their surface, which healthy cells do not express. When a T cell encounters such a cell, it can trigger an immune response that destroys it.
Cancer cells arise from normal cells through genetic mutations, and these mutations can produce abnormal proteins that T cells might recognise as foreign. In theory, the immune system should identify and eliminate nascent tumours before they become established. In practice, many cancers develop precisely because they find ways to evade this surveillance.
How cancers escape the immune system
Tumours employ several strategies to avoid immune destruction. One of the most important involves the PD-1/PD-L1 checkpoint. PD-L1 is a protein that signals "self" or "do not destroy" - normally expressed on healthy tissue to prevent the immune system from attacking the body's own cells. Many tumours learn to express PD-L1, exploiting this mechanism to disguise themselves as harmless.
When a T cell's PD-1 receptor binds to PD-L1 on a tumour cell, it receives an inhibitory signal: stand down. The T cell does not attack. The tumour evades detection not by hiding, but by actively suppressing the immune response directed at it. This is what makes the PD-1/PD-L1 pathway such a significant therapeutic target.
What pembrolizumab does
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor on T cells. By occupying PD-1, it prevents PD-L1 from delivering its inhibitory signal. The T cell remains activated and is able to recognise and attack the tumour. The analogy often used is releasing a brake - pembrolizumab does not activate the immune system directly, it removes an obstruction that the tumour had put in place.
This is why the treatment is described as immunotherapy rather than chemotherapy. It does not kill cancer cells directly. It restores the immune system's ability to do so itself.
Why response varies between patients
Not every patient responds to pembrolizumab. The effectiveness of the immune response depends on several factors: how many tumour-associated antigens are present (higher mutation burden generally means more targets), whether T cells are present in or around the tumour, and how strongly the tumour relies on the PD-1/PD-L1 pathway to evade detection. PD-L1 expression is a proxy for the last of these factors - which is why it is the primary eligibility biomarker. But it is not perfect, and the biology is more complex than any single test can capture.
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