Events
O xoves 3 de abril de 2025, Fernando Torres Andón (Investigador Miguel Servet. Grupo de Investigación de Oncoloxía, Fundación Pública Galega de Investigación Biomédica, Complexo Hospitalario Universitario de A Coruña) ofrecerá o seminario “Macrophage Reprogramming for Cancer Treatment" dentro do ciclo CINBIO Seminar Programme.
Será ás 11:00 horas na Sala de seminarios de Torre CACTI.
ABSTRACT:
The stroma of solid tumors is populated by myeloid cells, which mostly represent macrophages. Tumor-associated macrophages (TAMs), strongly influenced by cancer cell-derived factors, are key drivers of immunosuppression and support tumor growth and spread to distant sites. Increasing evidence demonstrates their ability to hamper cancer patients' response to most treatments currently applied in the clinic, including immunotherapy. Therefore, strategies to counteract negative effects of TAMs are nowadays gaining momentum at preclinical, translational, and clinical levels.
We have recently demonstrated the ability of poly(I:C) and/or R848, agonists of TLR3 and TLR7/8 respectively, to reprogram TAMs into antitumor effector cells, and also the efficacy of Stattic and/or Galunisertib, inhibitors of STAT3 and TGF-β pathways respectively, to inhibit immunosuppression by cancer cells and/or TAMs. The best combinations of these drugs were encapsulated in nanoemulsions or polymeric nanocapsules for improved TAM-targeting, biodistribution and higher accumulation in the primary tumor. These NPs were characterized for their physicochemical properties and also tested in vitro using primary human macrophages. For in vivo evaluation, subcutaneous and orthotopic murine models of lung cancer (CMT167) were used, showing antitumoral efficacy and TME reprogramming as evaluated by FACS, RNA analysis and multiplex immunofluorescence. Protamine-NCs-loaded with poly(I:C)+R848 and coated with an additional layer of hyaluronic acid functionalized with mannose were used to target the CD206 receptors, showing antitumoral efficacy mediated by TAM reprogramming. Experiments performed in IFN-γ KO mice and immune deficient mice (NSG and Balb/c nude) revealed that a fully functional immune system is crucial for the response to the treatment. The intravenous administration of the poly(I:C)+R848 combination significantly reduced the growth of primary tumors, evaluated in orthotopic models of lung cancer, fibrosarcoma, breast cancer and glioma. Notably, lung metastasis was prevented by intravenous poly(I:C)+R848 treatment both in the fibrosarcoma and in the breast cancer models. This research also highlighted the importance of a functional immune system for treatment efficacy.
We have also initiated a project on the development and evaluation of monocyte CAR-M cell therapy for the treatment of lung cancer. We have designed the first generation of plasmids and performed in silico studies to select the combination of targets with the highest affinity for the EGFR/MET antigens in lung cancer cells. Ongoing experiments are warranted to tested the efficacy and safety of this new monocyte-based therapy in resistant lung cancer.
Overall, our research demonstrates the promising potential of macrophage-targeted strategies, including nanoparticle-mediated drug delivery and CAR-M cell therapy, for treating resistant solid tumors.
BIO:
Fernando Torres Andón is Miguel Servet researcher at the Oncology Research Group of the Galician Public Foundation for Biomedical Research (“INIBIC”) and the University Hospital Complex of A Coruña (“CHUAC”) (A Coruña, Spain). He works on the development and evaluation of new antitumor immunotherapies, focusing on the study of tumor-associated macrophages (TAMs) in resistance to current therapies and new therapeutic strategies for their reprogramming. He holds a degree in Pharmacy from the “USC” and completed his doctoral thesis, "Evaluation of new compounds as potential antileukemic agents" at the “ULPGC”. He completed a postdoctoral fellowship in Molecular Nanotoxicology at the “Karolinska Institutet”, studying the interactions between nanomaterials and the innate immune system. He worked at the “Humanitas Clinical Institute” and “USC” using combinations of toll-like receptor agonists, either free or encapsulated into nanostructures, to enhance their release to TAMs and stimulate their antitumor activity in solid tumors.
