Immunotherapy and PD-L1: Association between circulating tumor cells (CTCs) and treatment efficacy
From the patient’s perspective, this article interprets the immune escape mechanism, its therapeutic applications, and the value of CTCs in predicting treatment efficacy.
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Cancer treatment has evolved dramatically over the past decades. Chemotherapy was once the cornerstone of therapy, but its lack of selectivity caused severe side effects. Targeted therapy improved precision, yet only benefits the small group of patients with specific driver mutations. In the 21st century, the rise of immunotherapy has completely reshaped oncology. In particular, PD-1/PD-L1 checkpoint inhibitors have given late-stage patients hope of longer survival and better quality of life even after other treatments have failed. This article examines the clinical significance of PD-L1 and immunotherapy from a patient’s perspective and explores in depth the relationship between circulating tumor cells (CTCs) and immunotherapy efficacy.
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PD-L1 and the Immune Escape Mechanism
One of the main reasons cancer cells can continue to grow and spread inside the body is their ability to evade the immune system. Research has shown that cancer cells express a protein called PD-L1. When PD-L1 binds to the PD-1 receptor on the surface of immune cells, the immune cells effectively “lose their ability to attack.” This mechanism is like a protective shield that prevents the immune system from recognising cancer cells as enemies.
This discovery not only revealed one of the key reasons cancer is so hard to cure but also opened an entirely new therapeutic avenue. In 2018, the Japanese scientist who elucidated the PD-1 pathway received the Nobel Prize in Physiology or Medicine, underscoring the profound impact of this breakthrough.
The core concept of immunotherapy is “releasing the brakes on the immune system.” PD-1 or PD-L1 inhibitors block the interaction between cancer cells and immune cells, allowing T-cells to regain their alertness and killing power.
Unlike chemotherapy or targeted drugs that directly attack the tumour, immunotherapy works indirectly by unleashing the patient’s own immune system to clear cancer cells. This approach brings new hope because its effect is not transient; once the immune defence is reactivated, it may provide long-term surveillance against cancer cells.
How Immunotherapy Works
Comparison of Chemotherapy, Targeted Therapy, and Immunotherapy
Traditional chemotherapy kills cancer by destroying rapidly dividing cells but lacks selectivity, so patients often suffer hair loss, nausea, and severe immunosuppression. Targeted therapy focuses on specific genetic mutations or proteins, causing less damage to normal cells, but only patients with the corresponding mutations can benefit.
Immunotherapy is different: it does not directly confront cancer cells but restores the natural function of immune cells. For patients, this feels less like “poisoning the tumour” and more like rebooting the body’s own defence system.
Side Effects of Immunotherapy: New Challenges and Opportunities
The side-effect profile of immunotherapy differs from chemotherapy. Studies show that fatigue, loss of appetite, nausea, and diarrhoea occur less frequently than with chemotherapy. However, immunotherapy introduces a new category of challenge: immune-related adverse events. Some patients develop immune-mediated pneumonitis, colitis, or thyroid dysfunction. Although these events are uncommon in the overall population, when they occur they may require steroids or immunosuppressants. Patients on immunotherapy must therefore remain under close medical supervision and report new symptoms promptly.
Indications for Immunotherapy
Compared with targeted therapy, immunotherapy has a much broader scope. PD-1/PD-L1 inhibitors have demonstrated efficacy across many cancer types, including lung cancer, melanoma, bladder cancer, head and neck cancer, gastric cancer, colorectal cancer, breast cancer, and prostate cancer. This means that even patients without a specific driver mutation may still benefit from immunotherapy.
How to Predict Response to Immunotherapy?
Because not every patient benefits, pre-treatment prediction is critical. The two main approaches currently used are:
- Genomic testing Measuring tumour mutational burden (TMB). The more mutations, the easier it is for the immune system to recognise cancer cells, increasing the likelihood of response.
- PD-L1 protein expression testing Examining PD-L1 levels in tumour tissue. PD-L1-positive patients generally respond better to PD-L1 inhibitors, with higher chances of tumour shrinkage.
Limitations of Tissue-Based Testing
Although tissue testing is the standard for predicting immunotherapy response, it has clear drawbacks. Archived samples may suffer PD-L1 protein degradation, and cancer cells are highly dynamic: PD-L1 expression can change over time and with treatment.
This means results from an initial biopsy may no longer reflect the current disease state. When fresh tissue is unavailable, accurate prediction becomes impossible.
The Link Between Circulating Tumor Cells (CTCs) and Immunotherapy
Circulating tumor cells (CTCs) are cancer cells that have detached from the primary tumour or metastases and entered the bloodstream. To patients, they are like “messengers floating in the blood,” carrying the tumour’s genetic, protein, and biological characteristics. With advances in liquid biopsy technology, CTCs are now widely used for early detection, monitoring, efficacy evaluation, and prognosis.
Their value is especially pronounced in immunotherapy. Traditional tissue biopsies sample only one location and cannot capture tumour heterogeneity or dynamic molecular changes. In contrast, CTCs in the blood provide an immediate, real-time picture of the entire tumour burden.
For PD-L1 expression in particular, CTCs add tremendous clinical value. Detecting PD-L1-positive CTCs in the blood usually indicates that the cancer is actively suppressing the immune response via the PD-L1 pathway. Patients with PD-L1-positive CTCs consistently show superior responses to PD-1/PD-L1 inhibitors. Multiple clinical studies have confirmed this:
- In melanoma, patients with PD-L1-positive CTCs had >80% progression-free rate at one year after immunotherapy, whereas most patients lacking PD-L1-positive CTCs progressed within the year.
- In gastric and colorectal cancer, patients with PD-L1-positive CTCs achieved objective response rates of ~48% vs only 14% in those without.
- In anal cancer studies, almost all patients with dramatic responses had detectable PD-L1-positive CTCs; non-responders rarely did.
These data show that PD-L1-positive CTCs are not only a real-time marker of tumour activity but are emerging as a powerful predictive tool for immunotherapy success. For patients, this is a breakthrough: a simple blood draw can provide highly relevant information about treatment likelihood without repeated invasive biopsies. Moreover, CTCs enable continuous monitoring during therapy. Changes in CTC count and PD-L1 expression after starting immunotherapy reflect real-time response. A decrease in CTC numbers or loss of PD-L1 usually signals treatment is working; rising CTCs may indicate progression or emerging resistance. This “real-time monitoring” capability is invaluable for patients requiring long-term management. Overall, detection of CTCs — especially PD-L1-positive CTCs — is rapidly becoming a cornerstone of personalised immunotherapy management, moving treatment from trial-and-error toward evidence-based decisions.
Patient Perspective: Hope and Challenges
From a patient’s viewpoint, immunotherapy is a double-edged sword. On one hand, it breaks through the limitations of conventional therapy, offering late-stage patients a real chance at longer life and better quality. On the other hand, patients face real-world hurdles: ● Extremely high cost — unaffordable for many ● Response is not guaranteed — some patients gain nothing ● Immune-related side effects can be unpredictable and life-threatening if not managed swiftly
Patients must therefore discuss thoroughly with their doctors, weighing disease status, financial situation, and test results before deciding.
Conclusion and Future Outlook
Immunotherapy has become a landmark breakthrough in cancer care, and PD-1/PD-L1 inhibitors in particular have transformed oncology. From the patient’s perspective, it is more than just another drug — it is a strategy to reboot the body’s own immune defence. As circulating tumor cell (CTC) technology continues to mature, clinicians will be able to predict immunotherapy response in a more dynamic, real-time manner, enabling truly personalised treatment decisions. In the future, the key challenges will be improving response rates, reducing costs, and safely managing immune-related toxicities so that immunotherapy can reach more patients.
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