Newcastle University Breakthrough Identifies New Treatment for ICB-Resistant Skin Cancers

Newcastle University Breakthrough Identifies New Treatment for ICB-Resistant Skin Cancers

(IN BRIEF) Researchers at Newcastle University have discovered a new biological mechanism explaining why some patients do not respond to immune checkpoint blockade (ICB) therapy for solid cancer tumors. They identified T regulatory cells (Tregs) as key drivers of ICB resistance and introduced a promising new combination treatment involving anti-CD30. This combination therapy has shown potential in overcoming resistance in metastatic skin cancers and could be beneficial for other solid cancers. The study highlights the need for personalized therapies and opens up new avenues for treating patients with advanced, ICB-resistant cancers.

(PRESS RELEASE) NEWCASTLE, 3-Jun-2025 — /EuropaWire/ — Newcastle University researchers have unveiled a groundbreaking discovery that explains why some patients do not respond to immune checkpoint blockade (ICB) therapy for solid cancer tumors and have identified a promising new combination treatment. The findings, published in Nature Immunology, shed light on the biological mechanisms responsible for ICB resistance and offer a new strategy to overcome resistance in metastatic skin cancers and potentially other solid cancers.

Dr Shoba Amarnath, Reader in Immune Regulation at Newcastle University

Dr. Shoba Amarnath, Reader in Immune Regulation at Newcastle University and the lead researcher of the study, explained that the new mechanism identified will help distinguish patients who are unlikely to respond to single-agent ICB treatments like anti-PD1 antibody therapy. The team discovered that these patients are more likely to benefit from a new combination therapy involving anti-CD30. “By adding anti-CD30 to the treatment regimen, we can improve the response to cancer therapy and avoid costly delays in treatment,” said Dr. Amarnath.

The study focused on skin cancers, but Dr. Amarnath and her team believe the new combination treatment will also benefit patients with other solid cancers, including lung, bowel, and pancreatic cancers, who are currently not responding to ICB monotherapy. The research found that ICB resistance is linked to the activity of a type of immune cell called T regulatory cells (Tregs). When the PD-1 protein is blocked on Tregs alone, it paradoxically promotes cancer growth, highlighting the critical role of Tregs in ICB resistance.

The researchers used an innovative mouse model designed specifically to study ICB resistance, in combination with human skin cancer samples, to demonstrate how ICB therapy induces the expression of alternate checkpoint proteins in Tregs, driving tumor growth. The team discovered that targeting CD30, an immune suppressive protein, could overcome this resistance. The anti-CD30 immunotoxin Brentuximab Vedotin (BV), currently used in blood cancers, shows potential as a combination therapy for solid tumors.

A recent Phase II trial in the U.S. demonstrated the benefits of combining anti-PD1 ICB with BV for patients with refractory metastatic cutaneous melanoma, a melanoma that has spread and does not respond to standard treatments. This combination showed a 24% median survival benefit, offering a significant new treatment option for late-stage skin cancer patients.

Dr. Amarnath added, “Our ongoing research in the lab is uncovering new immune-specific and tumor growth proteins that are highly expressed in Tregs during ICB therapy. These Tregs also exhibit stem-cell-like properties, which open up exciting new possibilities for treatment.”

The study was funded by a range of organizations including the Research Councils UK, the Medical Research Council (MRC), the LEO Foundation, the Academy of Medical Sciences, the National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs), and the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC).

Reference: PD-1 receptor deficiency enhances CD30+ Treg cell function in melanoma. Nature Immunology. Shoba Amarnath: Newcastle University. DOI: 10.1038/s41590-025-02172-0

ICB

The use of immune checkpoint blockade (ICB) therapy in solid cancers has shown unexpected success in a significant minority of patients. However, resistance to ICB therapy affects more than 60% of cancer patients who are prescribed this medicine. These medicines are expensive and cause significant toxicity in non-responders.

ICB therapy, or immune checkpoint blockade, is a type of immunotherapy that aims to unlock the body’s natural immune system to attack cancer cells. It works by targeting and blocking specific “checkpoints” in the immune system that normally help to keep it in check, allowing T cells to recognise and destroy cancer cells more effectively.

ICB resistance understood
The scientists demonstrate that ICB resistance occurs due to their effect on a type of immune cell called T regulatory cells (Tregs). Selective blocking of the ICB protein PD-1 on Tregs alone paradoxically enhances cancer growth in these patients. They studied this using a new mouse model where PD1 deficiency was limited to Treg cells together with samples from human skin cancer patients to study ICB resistance. This new mouse was engineered by scientists at Newcastle University to specifically allow understanding of ICB resistance.

They found ICB therapy enhances the expression of several alternate checkpoint proteins in Tregs that drives enhanced cancer growth. In the paper they describe how targeting one of these immune suppressive proteins called CD30, can rescue, or overcome, checkpoint therapy resistance in skin cancer. As an opportunity for future study, an immunotoxin (an anti-CD30 immunotoxin, Brentoximab Vidotin; BV) targeting this protein is already available for treatment of blood cancers and the team believe this has potential as a combination therapy for other solid cancers.

There is also a significant development from a Phase II trial in the USA in patients who do not respond to ICB monotherapy. In the trial, combining anti-PD1 ICB and BV shows 24% median survival for refractory metastatic cutaneous melanoma, a  melanoma that has spread to other parts of the body and is not responding to standard treatments. This provides a significant lifesaving alternative for late stage skin cancer patients who do not respond to standard ICB regiments.

Dr. Amarnath added:  “Further progress in the laboratory has discovered new immune specific proteins and tumour growth proteins that have elevated expression in Tregs during ICB therapy. We also found that these Tregs show stem-cell like properties.

“Ongoing work in the laboratory includes understanding the function and potential therapeutic value of targeting these new proteins in Tregs in skin and other solid cancers.

“We are very excited to find all these new aspects in ICB resistance biology which will not be possible without this new murine model. We believe targeting immune molecules and tumor growth proteins, will significantly enhance the efficacy of ICB in solid cancers”.

Funding for the study came from RCUK,   Medical Research Council (MRC), LEO Foundation, Academy of Medical Sciences, the National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs) and the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC).

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SOURCE: Newcastle University