An international research consortium led by Newcastle University has identified the biological mechanisms underlying immune checkpoint blockade (ICB) therapy resistance and developed a promising combination treatment strategy that could transform outcomes for cancer patients who fail to respond to current immunotherapies.
The study, published in Nature Immunology and led by Dr. Shoba Amarnath, Reader in Immune Regulation at Newcastle University, addresses a critical clinical challenge: more than 60% of cancer patients prescribed ICB therapy do not experience meaningful clinical benefit from these expensive treatments that carry significant toxicity risks.
Unraveling the Mechanisms of ICB Resistance
The research team discovered that ICB resistance occurs due to the therapy's paradoxical effects on regulatory T cells (Tregs) within the tumor microenvironment. Using an innovative mouse model engineered specifically at Newcastle University, where PD-1 deficiency was confined to Treg cells, the scientists demonstrated that selective blocking of PD-1 on Tregs alone actually enhances cancer growth.
"Identifying this mechanism is important as it identifies patients who will not respond to single agent ICB treatment such as anti-PD1 antibody therapy, but are most likely to benefit from the new combination therapy that we have identified, anti-CD30," explained Dr. Amarnath.
The study revealed that ICB therapy inadvertently amplifies the expression of alternate immune checkpoint molecules on Tregs, particularly CD30, which enhances their suppressive capabilities and promotes immune evasion. This discovery challenges previous assumptions that blocking PD-1 universally enhances anti-tumor immunity.
CD30 Emerges as Therapeutic Target
CD30, traditionally recognized as a marker in hematologic malignancies such as Hodgkin lymphoma, emerged as a crucial immunosuppressive axis in solid tumors resistant to ICB. The researchers demonstrated that deploying an anti-CD30 therapeutic could reverse resistance and suppress tumor growth in preclinical melanoma models.
The therapeutic potential of this approach is supported by existing clinical infrastructure, as Brentuximab Vedotin (BV), an anti-CD30 immunotoxin, is already available for treating blood cancers and could be repurposed for solid tumor combination therapy.
Clinical Validation in Melanoma
A Phase II trial conducted in the United States provided compelling clinical evidence for the combination approach. The trial evaluated anti-PD1 ICB combined with Brentuximab Vedotin in patients with refractory metastatic cutaneous melanoma—a notoriously incurable skin cancer subtype that has spread beyond the primary site and failed conventional therapies.
The trial demonstrated a 24% median survival advantage in these patients, representing a significant breakthrough for late-stage melanoma treatment and offering a tangible lifeline for individuals facing therapeutic dead-ends with ICB monotherapy resistance.
Broader Implications Across Cancer Types
The implications of targeting CD30+ Tregs extend beyond melanoma to other solid tumors where immune evasion remains a formidable challenge. Dr. Amarnath speculates that cancers of the lung, bowel, pancreas, and other organs sharing similar immunological vulnerabilities could derive substantial benefit from this combinatorial approach.
"Although our work was limited to skin cancer, we believe this new combination treatment will also benefit patients with lung, bowel, pancreatic and other solid cancers who are currently not responding to treatment with ICB monotherapy," Dr. Amarnath noted.
Advanced Molecular Insights
The team's ongoing laboratory investigations have revealed that Tregs in the context of ICB resistance acquire stem-cell-like properties and show upregulation of both immune modulatory and tumor-promoting proteins. This phenotypic plasticity may underpin their formidable capacity to shield tumors from immune attack.
The sophisticated murine model engineered at Newcastle University provided unprecedented insight into cellular and molecular networks within the tumor microenvironment, highlighting spatial organization of immunosuppressive Treg subsets and their functional impact on anti-tumor immunity.
Future Research Directions
The research team continues to identify additional targetable molecules that could synergize with existing immunotherapies, aiming to broaden and deepen clinical responses. Their work focuses on understanding the function and potential therapeutic value of targeting newly discovered proteins in Tregs across 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," Dr. Amarnath stated.
The research was supported by multiple prestigious funding bodies including the Medical Research Council, LEO Foundation, Academy of Medical Sciences, and the National Institute for Health and Care Research Newcastle Biomedical Research Centre, underscoring its importance in addressing the urgent medical need for solutions to ICB therapy resistance.
