Immune Cell Differences Predict Skin Cancer Treatment Outcomes

Melanoma patients may carry clues in their blood that reveal how well their immune systems are responding to immunotherapy, according to a new study led by researchers at King’s College London. The research found that coordinated changes in two major immune-cell populations—B cells and T cells—were associated with survival, treatment response and immune-related side effects. The findings raise the possibility that a blood test could one day help doctors identify which patients are most likely to benefit from checkpoint inhibitor therapy and who may require closer monitoring.

Melanoma is the fifth most common cancer in the United Kingdom and one of the most dangerous forms of skin cancer when it spreads beyond the skin. Surgery can be curative when the disease is detected early, while advanced melanoma may be treated with targeted drugs or immunotherapy. Checkpoint inhibitors have transformed care by releasing molecular brakes that normally restrain T cells, allowing these immune cells to recognise and attack tumour cells. Yet the treatment is far from universally effective: nearly half of patients do not obtain meaningful benefit, while some develop serious inflammatory side effects as the immune system attacks healthy tissues.

The new study focused on the adaptive immune system, the branch of immunity that develops highly specific responses to foreign or abnormal targets. T cells can directly kill cancer cells or coordinate broader immune activity, while B cells produce antibodies and can also present tumour-related antigens to T cells. Although B cells have historically received less attention in cancer immunology than T cells, growing evidence suggests that they can influence whether immunotherapy succeeds. The King’s-led team examined both cell types together, tracking how their activation states changed during treatment.

Researchers analysed blood samples from 24 people with stage 2 to stage 4 melanoma who were receiving checkpoint inhibitor immunotherapy at Guy’s and St Thomas’ NHS Foundation Trust. Samples were collected before treatment and at two time points during therapy, including within the first six weeks. Blood from 25 healthy volunteers was also assessed for comparison. Instead of examining only broad cell categories, the scientists used mass cytometry, a highly multiplexed technology that measures numerous proteins and other characteristics on individual cells simultaneously.

Mass cytometry enabled the team to distinguish rare immune-cell populations that would be difficult to identify using conventional methods. The researchers could determine whether B and T cells displayed signs of activation, maturation, proliferation or impaired function, then follow those features over time. This approach revealed substantial variation between patients even before treatment began, suggesting that the immune system’s starting condition may influence how an individual responds to immunotherapy.

Patients with favourable outcomes tended to show renewed activation and expansion of both B-cell and T-cell populations during the early stages of treatment. This pattern was interpreted as evidence of immune reinvigoration: checkpoint inhibitors appeared to restore or amplify immune responses that had been suppressed by the tumour or by chronic exposure to tumour antigens. The coordinated behaviour of the two cell types was particularly important, because effective anti-cancer immunity often depends on communication between antibody-producing B cells, antigen-presenting cells and tumour-killing T cells.

In contrast, patients whose blood continued to contain immature or poorly functioning B-cell populations during treatment generally experienced less favourable outcomes. Weaker baseline B-cell and T-cell anti-cancer responses were also associated with poorer survival after therapy. Certain T-cell subtypes appeared to be linked with treatment-related toxicity, indicating that the same immune activation that can damage tumours may sometimes trigger inflammation in healthy organs. However, the researchers emphasised associations rather than definitive proof that these cell populations directly cause treatment success or side effects.

The results are promising because blood sampling is substantially less invasive than repeated tumour biopsies. A future immune-monitoring test could potentially measure B-cell maturation, T-cell activation and changes in immune-cell abundance before and shortly after therapy begins. Such information might help oncologists decide which patients should continue a treatment, receive intensified surveillance or be assessed early for immune-related complications. Nevertheless, the study was small, and the findings must be validated in larger patient groups before they can be used to guide clinical decisions. Immune profiles may also differ between cancer types, treatment combinations and disease stages.

Lead author Lucy Booth, a PhD student at King’s College London’s St John’s Institute of Dermatology, said the work highlights the importance of studying B cells alongside T cells. Professor Sophia Karagiannis, Professor of Translational Cancer Immunology and Immunotherapy at King’s, said that analysing the two adaptive immune-cell populations over time showed how they simultaneously change during treatment. The group previously identified blood-based B-cell markers associated with immunotherapy toxicity and treatment response, and now plans to investigate how B and T cells behave inside tumours themselves. The researchers also hope to repeat the analysis in larger cohorts and in other cancers, including triple-negative breast cancer, where treatment options remain limited.

Web References: Journal for ImmunoTherapy of Cancer study; King’s College London research background

References: DOI: 10.1136/jitc-2026-015585