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An international research identifies a biomarker predicting prognosis for immunotherapy-treated patients with advanced cancer

Researchers from Cima and the Clínica Universidad de Navarra show that high IL-8 levels are linked to worse patient response to the treatment

Descripcion de la imagen
José Luis Pérez-Gracia, Álvaro Teijeira, Ignacio Melero, Miguel Fernández de Sanmamed and Saray Garasa, Cima and Clinica Universidad de Navarra researchers team. FOTO: Manuel Castells
Descripcion de la imagen
Microscopic picture with multiplex immunofluorescence on tumor tissue with IL-8 production (stained red) and attracting neutrophils (pink/white). FOTO: Cima
18/05/20 13:07 María Pilar Huarte

Therapies that stimulate the immune system have become a standard treatment for many types of tumor. However, a high percentage of patients do not respond to the treatment, so it is fundamental to identify them early on, to avoid their unnecessary exposure to ineffective and potentially toxic drugs.

Researchers from Cima and the Clínica Universidad de Navarra have identified a biomarker that predicts the outcome for patients with advanced cancer treated with immunotherapy. The work, carried out in collaboration with Dr Kurt Schalper, from the University of Yale (USA) and the pharmaceutical company Bristol Myers Squibb (BMS), has been published in the most recent issue of the scientific journal Nature Medicine.

It is a large-scale retrospective study involving 1,344 patients with advanced lung cancer, melanoma and renal cancer. “The patients participated in four phase-3 clinical trials in which samples of serum and cancerous tissue were gathered. These patients were given an immunotherapy treatment (nivolumab) or a combination of two immunotherapy drugs (nivolumab and ipilimumab)”, as explained by Dr Ignacio Melero, codirector of the Immunology Department of the Clínica Universidad de Navarra and a senior researcher at Cima.

The research shows that high levels of a substance of the system (cytokine IL-8) generate a tumoral microenvironment resistant to immunotherapy which is, consequently, disadvantageous for the patient. “As a result, patients with high IL-8 levels do not respond to the treatment and their evolution is worse. Therefore, IL-8 is seen to be a very useful biomarker to direct a more suitable early treatment for each patient”, Dr. Melero stated.

Together with this work, Nature Medicine has published another parallel article by the Sanjeev Mariathasan (Roche-Genentech) group, which comes to the same conclusions. “The journal adds a highlighted comment on both works written by the oncologist Choueiri from the Dana-Farber Cancer Institute (Harvard), in which he summarizes and contextualizes the importance of these findings", added the Cima and Clínica Universidad de Navarra researcher.

As Dr Miguel Fernández de Sanmamed, coauthor of the work commented, “IL-8 can attract an abundance of a type of leucocytes to the tumor , which may interfere with the beneficial immune response for the patient. In fact, in an international clinical trial, we are blocking IL-8 with a monoclonal antibody (HumaxIL-8) to restore the response capacity to immunotherapy”.

Tumor mechanisms and the immune system

In order to understand the mechanisms involved in the lack of response to immunotherapy in these patients, the study analyzed the role of neutrophils (the most abundant white blood cells in the blood). “We found that the cases with the worst post-treatment outcome showed an elevated expression of IL-8 and a great abundance of neutrophils within the tumor tissue”.

In parallel, the researchers from Cima and the Clínica Universidad de Navarra carried out experimental research on animal models to confirm the role of neutrophil interference with immunity towards cancer. “In this second study we found that the tumor cells, due to their production of IL-8, may create neutrophil extracellular traps (NETs), and so protect the malignant cells like a shield from the anti-tumoral mechanisms of the immune system”, said Dr Melero. “In this work, we have for the first time been able to analyze these phenomena using intravital microscopy. Specifically, we have observed the formation of NETs in tumors implanted in mice”, stressed Dr Álvaro Teijeira, first author of the work.

This study carried out in animal models with colorectal cancer, melanoma and breast cancer metastasis confirms that the inhibition of NETs in tumor tissue synergically elevates the benefits of immunotherapy. The results have been published in the scientific journal Immunity and again make the case for IL-8 blocking so as to improve the immunotherapy treatment. Dr Melero, the lead researcher in both works, states that “the results of the clinical trial combining IL-8 blocking with the pre-approved immunotherapies as the best treatment will be published in the coming months”.

  • Bibliographical reference:
    'Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors' https://www.nature.com/articles/s41591-020-0856-x

    CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity. Immunity. 2020 Apr 6. pii: S1074-7613(20)30089-3. doi: 10.1016/j.immuni.2020.03.001.

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