Funciones:
An FPIScholarship is offered to carry out a doctoral thesis in the Combined Strategies for Translational Immunotherapy Group of the Immunology Program framed in project PID2023-147515OB-I00 funded by MCIU/AEI/10.13039/501100011033 and FSE+ entitled:
Synergistic combinations for cancer Immunotherapy based on agonist immunotherapy agents and interference with pro-tumoral inflammation (SynerCombIT)
Transformative opportunities in the field of cancer immunotherapeutics usually stem from combinations involving agents of immunotherapy among themselves or in synergistic combinations with either chemotherapies or antiangiogenics. Such combined treatment approaches have already revolutionized the treatment of a good number of solid malignancies becoming the best treatment options for patients.
However, multiple lines of evidence show that there exist inflammatory responses in cancer-bearing hosts that act to curtail the efficacy of immunotherapy. Such deleterious activities are orchestrated by soluble mediators and are mainly mediated by myeloid leukocytes (tumor-associated macrophages and neutrophils). Over the recent years, we have performed innovative preclinical and clinical research with CD137 (4-1BB) agonists, cytokine-based approaches (chiefly including IL-12, IL-18, LT-Beta and IL-15, sFLT3L), local immunotherapies including TLR agonists and RNA-engineered T-cell transfer. The overarching goal of SynerCombIT is to use these novel approaches in conjunction with the interference of pro-tumoral inflammatory mediators, testing such therapeutic approaches against difficult-to-treat mouse cancer models to gauge their efficacy, while interrogating the key mechanisms underlying the synergistic effects. Our primary pro-inflammatory targets to be neutralized are TNFalpha, CXCR1/2 chemokines, prostaglandin-E2 or/and IL-6. We recently unveiled a key protumor immunosuppressive role of neutrophil extracellular traps (NETs) in cancer. We postulate that NETs, as induced by inflammatory mediators, interfere with the functional immune synapses of T and NK lymphocytes with the cDC1 dendritic cells that cross-present tumor antigens. SynerCombIT plans to interfere with neutrophil chemoattractant and NETosis in combination with other immunotherapy approaches. In collaboration with various leading pharmaceutical companies, we will also test the most promising combinatorial strategies on explanted tissue cultures from freshly excised human tumors and in immunologically humanized mouse models bearing human tumor xenografts. To achieve its objectives the project will rely on genetically modified mouse strains (with TCR or conditional fluorescent transgenes, DTR-depletable of leukocyte subsets, immunodeficient, etc.), multiplex tissue immunofluorescence, transcriptomics, multiphoton intravital microscopy, mRNA transient gene-transfer and a variety of in-vivo and ex-vivo functional immune assessments. The opportunity envisioned by SynerCombIT comes from established strategies to tamper with pro-tumor inflammatory mediators that can actually be repurposed from clinically successful approaches to treat autoimmune conditions and systemic inflammation. Amazingly, according to our published and preliminary data, blockade of some of these targets (i.e. CXCR2, TNF/TNFR1, IL6, PGE2) does not only prevent or ameliorate side effects but also synergistically enhances efficacy. Interrogating mouse tumor models is the main strategy to define the most efficacious synergistic courses and identify biomarkers to personalize therapies. This project proposal, as based on solid preliminary data, is preclinical but endowed with a truly translational ambition to benefit cancer patients in liaison with the pharmaceutical industry. SynerCombIT will deliver efficacious synergist treatment combinations, whose mechanisms will be meticulously studied with state-of-the-art methodologies.
Requisitos:
- Bachelor + Master's degree in Biology, Biochemistry, Medicine, or related fields.
- Previous experience in laboratory techniques related to immunology, cancer immunology, animal experimentation, cell culture, confocal microscopy and gene-transfer will be valued.
- Grade point average or higher on a 10 scale (desirable).
- Skills in data analysis and proficiency in statistical software.
- Ability to work in a team and communicate fluently in Spanish and English (min. B2 level)
Se ofrece:
4-year predoctoral contract in the Center for Applied Medical Research.
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