Understanding and Overcoming Resistance in Skin Cancer Immunotherapy

Recent research has shed light on why certain skin cancers do not respond to immunotherapy, specifically immune checkpoint blockade (ICB) treatments. Despite the success of ICB in some patients, over 60% of individuals with solid tumors experience resistance, rendering these therapies ineffective and leading to significant medical costs and potential toxicity. A study published in Nature Immunology by scientists at Newcastle University, UK, has uncovered critical mechanisms behind this resistance.

The key factor appears to be the role of T regulatory cells (Tregs) within the tumor microenvironment. These immune cells, which normally help maintain immune balance, can be exploited by tumors to suppress anti-cancer immune responses. When ICB therapies, such as anti-PD1 antibodies, are administered, they can inadvertently increase the expression of other immune-suppressive proteins on Tregs, like CD30, which promote tumor growth instead of eradicating it.

To explore this, researchers developed a specialized mouse model with PD-1 deficiency limited to Tregs, alongside analyzing human skin cancer samples. Their findings demonstrated that broad ICB treatment fosters an environment where Tregs upregulate alternate checkpoints, facilitating cancer progression. However, targeting CD30 with existing immunotoxin drugs, such as Brentoximab Vedotin, can counteract this resistance.

Further, a Phase II clinical trial in the United States has shown promising results, combining anti-PD1 therapy with BV (Brentoximab Vedotin) in patients with metastatic skin melanoma resistant to standard treatments. The combination resulted in a median survival rate of 24%, offering hope for late-stage skin cancer patients.

Dr. Shoba Amarnath, who led the research, emphasizes that understanding these mechanisms allows for the development of more effective, personalized treatment strategies. She highlights the potential for applying this approach to other solid cancers like lung, bowel, and pancreatic cancers. The findings suggest that combining immune checkpoint inhibitors with targeted therapies like anti-CD30 could significantly improve outcomes, reduce unnecessary toxicity, and optimize therapeutic costs.

Ongoing studies continue to investigate the complex behaviors of Tregs during immunotherapy, aiming to identify new immune-related proteins and tumor growth factors that could be targeted to boost treatment efficacy. This research signifies a significant step toward overcoming the hurdles of ICB resistance and advancing cancer immunotherapy.

Source: Medical Xpress