An international team of scientists from the UK and US has found that monitoring the activity of macrophages—a type of white blood cell that engulfs pathogens and cancer cells—can help predict how melanoma patients will respond to immunotherapy. This important discovery, published in the esteemed journal JCO Oncology Advances, will assist doctors in choosing the most effective treatments for their patients.
Immunotherapy is a potent treatment option for various cancers, including skin and kidney cancer. However, only about half of patients benefit from this therapy.
This uncertainty leads to a trial-and-error approach in selecting treatments, which can result in non-responsive patients experiencing side effects while their cancer goes unchecked, and potentially worsening their condition.
Researchers from the Universities of Bath (UK) and Stanford University (CA, USA) have studied new biomarkers—signs of the immune system’s activity—that may help identify melanoma patients who are more likely to respond positively to a specific immunotherapy known as TVEC.
TVEC is a modified oncolytic virus directly injected into melanoma tumors to trigger an immune reaction. While this treatment has been used for advanced melanoma cases, this research is the first to investigate its effectiveness in high-risk stage II melanoma patients at an early stage.
Previously, it was believed that TVEC worked by activating T cells—another type of white blood cell—leading them to attack cancer cells and reduce the size of melanoma tumors.
However, the research team discovered that neither the pre-existing nor the post-treatment T cell populations were linked to treatment outcomes. Instead, they observed that variations in macrophage activity were related to which patients had positive responses to the treatment.
Moreover, previous studies have focused on measuring protein markers like PD-L1 and analyzing the genes associated with T cells to determine the effectiveness of immunotherapy.
However, this recent research indicates that such methods do not accurately predict which patients will benefit from treatment.
Focusing on Activation, Not Just Amount
The researchers used a technique named iFRET, which assesses protein activation rather than just counting protein levels.
The study revealed that the presence of T cells showed inconsistent patterns concerning viral stimulation or tumor response before and after treatment. In contrast, significant macrophage infiltration was observed after treatment in responding patients, linked to very high activation across immune checkpoint regulators—proteins that help manage the immune system and prevent it from attacking healthy tissues.
The researchers aim to use their findings to create predictive tests that can identify which patients are likely to respond to this therapy, allowing doctors to customize treatments, thus saving time, minimizing side effects, and preventing the use of ineffective, expensive treatments.
Professor Banafshé Larijani, from the Department of Life Sciences and Director of the Centre for Therapeutic Innovation at the University of Bath, co-led the study. She explained: “We understand that individuals react to immunotherapy differently—sometimes tumors decrease in size, and in other cases, unfortunately, patients do not survive.”
“Our results indicate that merely assessing T cell activity is insufficient; we must thoroughly analyze the complete immune response environment to foresee how a patient will react to various treatments.”
“Our findings suggest that we should target macrophages in non-responsive patients to reprogram the tumor immune environment.”
“We hope our research will help doctors make informed choices about whether patients might benefit more from surgery or immune checkpoint blockade through immunotherapy.”
Dr. Amanda Kirane, Director of the Cutaneous Surgical Oncology Department at Stanford University School of Medicine and who led the clinical aspect of the study, stated:
“This study provides crucial insights linking pre-existing innate immune mechanisms to the capacity to respond to immune-stimulating therapies.”
“It also supports growing evidence of biological differences among patients who are more likely to respond to this immunotherapy—oncolytic viruses—compared to other types that focus on immune checkpoint regulators.”
“Finally, it sheds new light on the gap between measuring PD-L1 protein levels as a clinical marker and the activity of proteins within the tumor.”
“The insights obtained from iFRET-based immune activity measurements may provide vital information on why existing biomarkers have not yielded practical tests to assist patients in their treatment decisions.”
Looking ahead, the team plans to analyze all the cells involved in immune checkpoint interactions, aiming to improve patient classification and personalize medical treatment further.
