Physiopathology of chemokine receptor interactions

LKremer

 

Leonor Kremer

Group Leader

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Research summary

Our main research interest is to understand how chemokines mediate the interaction between tumour cells and their microenvironment, and how they participate in the control of tumour growth and progression. We study the contribution of chemokine receptors to cancer cell physiology, and evaluate their potential as antitumor targets.

 

Publications

Somovilla-Crespo B, Martín Monzón MT, VelaM, Corraliza-Gorjón I, Santamaria S, Garcia-Sanz JA, Kremer L. 92R Monoclonal Antibody Inhibits Human CCR9+ Leukemia Cells Growth in NSG Mice Xenografts. Front Immunol. 2018; 9:77.

Corraliza-Gorjón I, Somovilla-Crespo B, Santamaria S, Garcia-Sanz JA, Kremer L. New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness. Front Immunol. 2017; 8:1804

Santamaria S, Delgado M, Kremer L, Garcia-Sanz JA. Will a mAb-Based Immunotherapy Directed against Cancer Stem Cells Be Feasible? Front Immunol. 2017; 8:1509.

Vela M, Aris M, Llorente M, Garcia-Sanz JA, Kremer L. Chemokine receptor-specific antibodies in cancer immunotherapy: achievements and challenges. Front Immunol. 2015; 6:12

Chamorro S, Vela M, Franco-Villanueva A, Carramolino L, Gutiérrez J, Gómez L, Lozano M, Salvador B, García-Gallo M, Martínez-A C, Kremer L. Antitumor effects of a monoclonal antibody to human CCR9 in leukemia cell xenografts. MAbs 2014; 6:1000-12

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Funding

logo ministerio eco com FEDER

 

 

 

Convocatoria Retos-Colaboración 2015 con el objetivo de: Promover el desarrollo tecnológico, la innovación y una investigación de calidad. RTC-2015-3786-1: Desarrollo de anticuerpos terapeúticos anti-CCR9 para el tratamiento personalizado de tumores (TERPERAN).

 

ISCiii Proyecto concedido a José María Casasnovas Suelves y Leonor Kremer Barón. Ref. DTS15/00193: Obtención y caracterización de anticuerpos frente a la glicoproteina del Ebolavirus. Entidad financiadora: Instituto de Salud Carlos III. Importe: 50.600 €

PN2014, Fondo de Investigaciones Sanitarias (PI14/00703). Anticuerpos Anti-CCR9 para Inmunoterapia Antitumoral en Pacientes con Leucemia Linfoblástica Aguda de Inmunofenotipo T (LLAT). 2015-2017. IP: Dra. L. Kremer, CNB-CSIC.

 

 

FiguraKremer2015.jpgThe chemokines, small proteins with a central role in the maintenance of innate and acquired immunity, interact with specific G protein-coupled receptors and participate in the pathogenesis of inflammatory and infectious diseases as well as in cancer. Chemokines can help limit tumor development by increasing leukocyte migration to a tumor site and by inducing long-term antitumor immunity. Nonetheless, they can also facilitate tumor cell survival, proliferation, and metastatic potential. Tumor expression of a chemokine receptor directs metastasis preferentially to the organs in which the chemokine ligand is secreted, suggesting chemokine receptors as promising therapeutic targets.

Our main research interest is to determine how chemokines and chemokine receptors participate in the control of tumor growth and progression, and to evaluate their potential as antitumor targets. The use of specific monoclonal antibodies for chemokine receptor targeting allows us to block signaling by preventing ligand binding to its receptor, and to tag tumor cells and trigger a host immune response to them.

The chemokine receptor CCR9 is expressed primarily on thymocytes and in a small subset of intraepithelial lymphocytes; its only natural ligand, CCL25, is expressed mainly in thymus and by the small intestine. Its overexpression increases the migratory and invasive capacity of prostate cancer cells, directs ovarian cancer and melanoma metastases to the small intestine, and activates anti-apoptotic pathways that lead to survival and increased proliferation of leukemia cell lines. CCR9-mediated intracellular signaling activates the anti-apoptotic PI3K, Akt, PTEN, mTOR, ERK1/2 and GSK-3 pathways, and downregulates activation of caspase-3, leading to cell survival and increased proliferation.

We have generated and characterized mouse anti-human CCR9 monoclonal antibodies that reduced human T lymphoblastic cell tumors transplanted into mice by >85%. Tumor size reduction was concomitant with an increase in the fraction of apoptotic tumor cells and in tumor necrotic areas, as well as a decrease in the fraction of proliferating cells and in tumor vascularization. Our results suggest that CCR9-expressing tumors such as acute and chronic T cell lineage leukemia might be targeted with these antibodies.

 GrupoKremer2015Red 

Name
Position
Contact
Leonor Kremer Principal investigator
Isabel Corraliza Predoctoral student
Beatriz Somovilla Predoctoral student
María Lozano Technician
Mercedes Llorente Technician
Ana María García Cabrero Technician

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