Background and research accomplishmentsDuring my undergraduate thesis at the University of Chile, Chile, I acquired experience working with the zebrafish model. In particular, I characterized the role of the tumor-associated calcium signal transducer (tacstd) gene in the migration of a structure called the posterior lateral line (PLL) primordium (Villablanca et al., dev dyn. 2006). During my Ph.D. thesis in molecular medicine at S. Raffaele Vita-Salute University, Milan, Italy, I investigated novel mechanisms of tumor immune escape. I focused in cancer-dendritic cell (DC) interactions and I found that tumors produce and secrete Cholesterol metabolites inhibiting DC migration to the secondary lymphoid organs (SLOs). In an attempt to identify tumor-released factors involved in DC migration inhibition, I started collaboration with Dr. Miguel Allende (Universidad de Chile, Chile), in which we designed and validated an in vivo high-throughout screening approach for small molecules able to inhibit cell migration. This screening method was also awarded for patenting by the University of Chile (US$48,000). Furthermore, using this screening approach, we found that some retinoids inhibit the zebrafish PLL migration as well as murine DC migration to SLOs (Villablanca et al., j. leukoc. Biol. 2008). In addition, I discovered that tumor release LXR ligands able to inhibit both human and murine DC migration towards SLOs. I found that these molecules are crucial in the early stages of tumor immune escape. Blocking synthesis and function of these LXR ligands resulted in DC migration recovery with the consequent control of tumor growth. Importantly, we have demonstrated in vivo that tumor-derived oxysterols inhibit DC migration whereas genetically modified tumors producing inactive oxysterols do not (Villablanca et al, Nat. Med., 2010). In summary, I have acquired experience working with zebrafish, mouse and human cells in different fields such as developmental biology and tumor immunology, obtaining a substantial expertise in cell trafficking, nuclear receptors, tumor and DC biology.
Interested in how lymphocytes and DC acquire tissue-specific migratory capacity (“homing”) and how tissue-specific homing is related to tumor immune tolerance, I joined Dr. Mora’s laboratory, which has been a pioneer in deciphering the mechanisms controlling homing imprinting to the gut mucosa. Dr. Mora has recently discovered that DC from Gut-Associated Lymphoid Tissues (GALT-DC) imprint T and B cells with gut-homing properties, an effect that depends on the specific capacity of GALDT-DC to produce retinoic acid (RA), a vitamin A metabolite. During my postdoctoral training I have discovered that RA in cooperation with MyD88 signaling pathways are necessary and sufficient to induce gut-DC differentiation (Villablanca et al, Gastroenterology, 2011; Wang et al, J. Immunol, 2011). We have also demonstrated that Foxp3 T regulatory cells require gut homing molecules (e.g., CCR9) to establish oral tolerance (first co-author in Gastroenterology, 2011b). Furthermore, during my last two years of postdoctoral training I sought to understand the mechanism of intestinal DC reconstitution from bone marrow (BM) precursors. I found that DC precursors reconstitute the intestinal DC network in an integrin β7-dependent manner and that depletion of these cells results in disruption of oral tolerance (first author; manuscript under revision). Thus, during my postdoctoral training I have acquired a solid expertise in mucosal immunology, with specific experience in intestinal DC trafficking, development, and abilities to induce Foxp3 TREG and IgA class switching.
In the next future, I would like to establish my own group to investigate the interplay between tumor cells and the immune system, process that might result in immune tolerance. Interestingly, several mechanisms to induce immune tolerance to commensal bacteria in the gut has been found in tumors, such as the induction of IDO on DC or induction/recruitment of Foxp3 T regulatory cells. Hence, investigating the mechanism of tolerance induction in the gut might help us to find new mechanisms of tolerance induction by tumors. A key player are Dendritic Cells, which control effector and tolerogenic immune responses in both tumor and mucosal immunity. Interfering with DC recruitment to specific organs might result in an impaired generation of an efficient adaptive immune response. I have demonstrated that tumor block DC migration to lymph nodes in order to abolish tumor immune responses and currently I’m investigating how impaired DC migration to the intestine might result in exacerbation of Inflammatory Bowel Diseases (IBD). Thus, I believe DC migration, differentiation and recruitment can be exploited to guide effector/tolerogenic immune responses depending on the desired outcome. My goal will be to determine the factors and molecules required for proper DC differentiation and migration to specific organs and how tumor and/or the intestinal microenvironment might affect this process in order to induce and/or break immune tolerance.