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19/10/2021 - Press release

Utility of a new therapeutic target in the immunotherapy treatment of one of the most aggressive breast cancers is demonstrated

Natural killer cells, or NK, are part of the immune system and the body's defences against cells infected by viruses or tumours. Previous studies have shown the importance of these lymphocytes in the success of HER2-positive breast cancer-specific antibody treatments. Now, a new study published in the journal Cancer Immunology Research goes further, validating as a therapeutic target a molecule present on the surface of NK lymphocytes, a tool that makes them resistant to the immunosuppressive mechanisms of cancer cells. This could open up a new approach involving immunotherapy-based drugs for treating this type of tumour.

The work, carried out by the PhD student Mariona Cabo and led by Dr. Aura Muntasell, a member of the Immunity and Infection Research Group at the Hospital del Mar Medical Research Institute (IMIM-Hospital del Mar) and the Autonomous University of Barcelona, demonstrates the importance of the CD137 molecule, also known as 4-1BB, in boosting the antitumoural action of NK lymphocytes. By treating tumour samples in vitro, the study has demonstrated the potential of CD137 agonist drugs (drugs that increase the activation of the CD-137 molecule) to increase the clinical efficacy of specific antibodies in HER2-positive breast cancer through their action on NK lymphocytes. Researchers from Pompeu Fabra University, the CIBER on cancer (CIBERONC), the Centre for Applied Medical Research (CIMA), Clínica Universitaria de Navarra, IDIBAPS and the Medical Oncology and Anatomical Pathology departments at Hospital del Mar also collaborated in the study.

Image: NK cell. Source: IMIM.

Stimulating CD137 to boost immune activity and prevent tumour immunosuppression
Using various tools, the researchers were able to demonstrate how the action of the CD137 molecule, expressed in the membrane of NK lymphocytes, makes them resistant to the effects of another molecule present in the tumour environment, TGF-beta. TGF-beta has the ability to suppress lymphocyte function, preventing them from recognising and eliminating tumours. 

"Stimulating CD137 allows NK lymphocytes to develop resistance to inhibition by TGF-beta, so that they can continue to recognise and kill tumour cells in the presence of this molecule", explains Dr. Muntasell. To demonstrate this, the study used a developmental drug, an agonist antibody that stimulates CD137. "The combination of the therapeutic antibodies currently used in HER2-positive breast cancer, such as trastuzumab and pertuzumab, could gain clinical efficacy if they are combined with molecules or other therapeutic tools that stimulate the CD137 receptor on NK lymphocytes", adds the first author of the study.

Dr. Ignacio Melero, from the Centre for Applied Medical Research (CIMA) and Clínica Universitaria de Navarra, who is developing the CD137-specific antibody, explains that "At the moment, there are at least half a dozen agents in clinical cancer-treatment trials that exploit the stimulation of antitumoural lymphocytes by 4-1BB (CD137) receptor agonists. This work pioneers a functional connection between the potent immunosuppressant TGF-beta and 4-1BB in the context of Natural Killer cells. These findings are a step towards understanding some of the clinical benefits being observed in patients treated with these new immunotherapy drugs." Dr. Miguel López-Botet, coordinator of the Immunity and Infection Research Group at IMIM, immunologist at the Hospital del Mar and a lecturer at Pompeu Fabra University, adds that "The work, led by Dr. Muntasell, reflects the group's efforts to transfer our knowledge of NK cell biology to clinical practice. The success is the result of the collaboration established with the Oncology and Pathology departments at Hospital del Mar, as well as with Dr. Melero, an internationally renowned expert in antitumour immunotherapy."

Useful in other tumours
The discovery of how CD137 acts to activate the immune reaction is not limited to breast cancer. This mechanism may be useful in other types of tumours, such as colon or pancreatic cancer, in which there is a strong presence of the TGF-beta molecule, which prevents the action of NK lymphocytes. As Dr. Joan Albanell, head of the Medical Oncology Service at Hospital del Mar and coordinator of the IMIM Cancer Research Programme, points out, "The research reveals a connection between conventional HER2-positive breast cancer therapy with monoclonal antibodies and the induction in Natural Killer lymphocytes of molecules that activate the immune system. The availability of immunostimulatory antibodies that act on these molecules will allow the development of innovative and personalised therapeutic strategies, particularly aimed at reversing certain immunosuppressive tumour environments for which conventional therapy is insufficient." 

The study received funding from the Worldwide Cancer Research Foundation, the Spanish Association Against Cancer and the Health Research Fund of the Carlos III Health Institute (ISCIII). 

Personalised care and cutting-edge cancer research at Hospital del Mar

Personalised care for cancer patients at Hospital del Mar is provided through pioneering and cutting-edge work in multidisciplinary functional units specific to each type of tumour. The units, comprising professionals specialising in each cancer type, offer the best therapeutic options in a model of shared decision-making with the patient. Nurse managers guide patients through the diagnostic and therapeutic process. This quality care is combined with ground-breaking cancer research at the Hospital del Mar Medical Research Institute (IMIM) and an extensive programme of clinical trials. The research areas focus on furthering immunotherapy and liquid biopsy, searching for biomarkers and new therapeutic targets, and developing new surgery and radiotherapy strategies to improve efficacy and the quality of life of patients. This research generates almost 200 articles in scientific publications each year, two out of three of which are in high-impact journals. This state-of-the-art care and research are the basis for teaching excellence at the Hospital del Mar Campus.

Reference article
Cabo M, Santana-Hernández S, Costa-Garcia M, Rea A, Lozano-Rodríguez R, Ataya M, Balaguer F, Juan M, Ochoa MC, Menéndez S, Comerma L, Rovira A, Berraondo P, Albanell J, Melero I, Lopez-Botet M, Muntasell A. CD137 costimulation counteracts TGFβ inhibition of NK-cell antitumor function. Cancer Immunol Res. 2021 Sep 27:canimm.0030.2021. doi: 10.1158/2326-6066.CIR-21-0030. Epub ahead of print. PMID: 34580116.
 

Research team.

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