A study published in « Nature Cancer»Seems to explain one of the greatest challenges of immunotherapy:why some people with cancer respond to treatment, while others do not?.
Researchers from UCLA Jonsson Comprehensive Cancer Center (USA) have identified which patients with lung cancer will be able to obtain lower results with immunotherapy, one of the most effective treatments against cancer.
In their work, scientists have seen that patients with a particular type of human leukocyte antigen (HLA), a protein scaffold involved in the presentation of protein fragments described as peptides to the immune system, are the best candidates to benefit from immunotherapy.
The data focused on a type of HLA called B44, which is present in about half of all people. In melanoma, HLA-B44 patients tend to do well with immunotherapy, but in non-small cell lung cancer, the most common type of lung cancer, most people with HLA-B44 do not respond as well as people without HLA-B44.
In the study, the authors found that the different responses were driven by the different types of mutations that are common in each of the cancer subtypes.
«Finding out that immunotherapy in HLA-B44 patients works differently in non-small cell lung cancer than in melanoma prompted us to dig deeper into how HLA-B44 works“Says lead author Amy Cummings. “In general, you would think that in two types of cancers that generally respond well to immunotherapy there would be similar principles in terms of the characteristics of the patients who benefit, but that is not the case.”
“From the moment we discovered the contradictory results in HLA-B44 patients with melanoma and non-small cell lung cancer, we were fascinated by the mechanism that could explain this situation,” advances lead author Edward Garon. “And while we were looking for this explanation, we got important information about how the immune system identifies tumors.”
To investigate the role of HLA in the response to immunotherapy, researchers performed the sequencing of the Whole exome in blood samples and melanoma tumors and non-small cell lung cancers. Whole exome sequencing examines the genes that make proteins and the mutations that may be present in cancer.
Mutations in protein-making genes often produce a peptide that the immune system can recognize as abnormal, called a neoepitope. The team predicted the neoepitopes generated by the patients’ mutations to identify which one would most effectively bind HLA-B44 and present itself to immune cells. Using this information, they analyzed the results of treatment, including survival.
In this way they found that patients with HLA-B44 non-small cell lung cancer, only those who had neoepitopes similar to those found in melanoma obtained good responses to immunotherapy. What’s more, those responses tended to be long-lasting, meaning that patients with non-small cell lung cancer with HLA-B44 and melanoma-like neoepitopes had responses to immunotherapy that lasted for years, some more than five.
“This has many implications for the way we conduct clinical trials and can help us to stratify patients much better in terms of their likelihood of response to immunotherapy,” adds Cummings.
“We hope to take advantage of these findings to design therapies that can further enhance the immune response against tumors in specific patients», adelanta Cummings.