Physiopathology of Innate Immunity

The general aim of our laboratory is focused on the study of different factors that regulate the activity of the cells of the innate immunity known as natural killer cells or NK cells in different physiopathological situations. This interest originates in the fact that NK cells are essential players during immunity against viruses and tumors, and in shifting the adaptive immune response towards a Th1/pro-inflammatory profile. Our studies have translational implications because the knowledge that we intend to generate, we aspire to contribute with the development and optimization of therapeutic strategies for patients with cancer and pathologies with immunological background trough the manipulation of the biological activity of NK cells.

Physiopathology of Innate Immunity

  • Principal Investigator

    Dr. Norberto W. Zwirner Currículum Vitae

    Principal Investigator. National Research Council (CONICET)

    Associate Professor, Immunochemistry, Department of Biological Chemistry, School of Natural and Exact Sciences, University of Buenos Aires

  • Team

    Mercedes Beatriz Fuertes, PhD (Associate Researcher CONICET)

    Carolina Inés Domaica, PhD (Assistant Researcher CONICET)

    Nicolás Ignacio Torres (PhD student and fellow CONICET)

    Sol Yanel Núñez (PhD student and fellow CONICET)

    Florencia Secchiari (PhD student and fellow CONICET)

    Jessica Sierra (PhD student and fellow CONICET)

Research focus

Natural killer (NK) cells are characterized by their ability to recognize and eliminate tumor cells and cells infected with different viruses, thus playing a crucial role in anti- tumor and anti-viral immunity. In addition, NK cells have the particular capacity to shift the adaptive immune response towards a Th1/proinflammatory and cytotoxic profile because they establish a cross talk with dendritic cells that instruct the latter to promote the differentiation of CD4 T cells into Th1 cells and the generation of cytotoxic CD8 T cells (CTLs). These pivotal functions of NK cells make them a very attractive target to develop immunostimulatory strategies using endogenous or exogenous factors aimed at exploiting their immunoregulatory capacities in different physiopathological situations. In this context, our studies are focused on the investigation of:

- the mechanisms that regulate the cross talk between NK cells and different dendritic cells;

- the mechanisms that regulate the cross talk between NK cells and myeloid-derived suppressor cells expanded during tumor growth;

- the role of NK cells in the induction of CTLs against tumors;

- the characterization of the glycophenotype of NK cells and the role of specific ligands of different glycans in the regulation of NK cell effector functions;

- the role of novel cytokines on NK cell function; and

- novel tumor immune escape mechanisms that compromise NK cells and contribute to tumor progression and metastases in patients with renal cell carcinoma and acute myelogenous leukemias.

Collaboration with the Children´s Hospital “Ricardo Gutiérrez” of Buenos Aires

We actively collaborate with the Immunology Section of the Children´s Hospital “Ricardo Gutiérrez” of Buenos Aires in order to characterize novel clinical entities in patients suspected to suffer primary immunodeficiencies that compromise NK cells to improve the selection of the most appropriate therapy in such patients.

Collaboration with CEMIC

Renal cell carcinoma is a type of cancer with a high incidence in our population. The most frequent renal cancer is the clear cell carcinoma (which represents more than 80% of the kidney tumors) and is the one with the highest metastatic capacity. Surgery is still the best therapeutic option for the patients. Besides a critical role of NK cells during tumor immunosurveillance, persistent tumor growth in immunocompetent patients is frequently observed (either due to the re-emergence of the primary tumor or the appearance of metastases), which is due to the intrinsic resistance of tumor cells to immune-mediated rejection and the development of tumor immune escape mechanisms. As the mechanisms that lead to an altered NK cell function remain ill-defined, we established collaboration with surgeons of the Urology Section of the Surgery Department of CEMIC in order to investigate such tumor immune escape mechanisms.

Collaboration with the Italian Hospital of Buenos Aires

Myeloblastic leukemias are the most frequent leukemia in the adult and present a high rate of relapse. This indicates a necessity to develop novel therapeutic approaches. One mechanism that has been proposed to explain the relapse is the immunosuppression induced by the leukemic blasts. Patients with myelogenous leukemia and high risk myelodysplastic syndrome exhibit phenotypic and functional defects in their NK cells but the underlying mechanisms remain poorly defined. Through collaboration with physicians of the Hematology Section of the Italian Hospital of Buenos Aires we investigate the mechanisms that lead to such altered NK cell phenotype and function in these patients.

Publications (Since 2007)

1. Cytokine-driven regulation of NK cell functions in tumor immunity: role of the MICA-NKG2D system. Zwirner NW, Fuertes MB, Girart MV, Domaica CI and Rossi LE. Cytokine and Growth Factors Review (USA). Review. 18:159-170 (2007).

2. Engagement of TLR3, TLR7 and NKG2D regulate IFN-g secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with suboptimal doses of IL-12. Girart MV, Fuertes MB, Domaica CI, Rossi, LE and Zwirner NW. J. Immunol. 179:3472-3479 (2007).

3. Intracellular retention of the NKG2D ligand MICA in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity. Fuertes MB, Girart MV, Molinero LL, Domaica CI, Rossi LE, Barrio MA, Mordoh J, Rabinovich GA and Zwirner NW. J. Immunol. 180:4606-4614 (2008).

4. Tumor-experienced T cells promote NK cell activity through trogocytosis of NKG2D and NKp46 ligands. Domaica CI, Fuertes MB, Rossi LE, Girart MV, Ávila DE, Rabinovich GA and Zwirner NW. EMBO Rep. 10:908-915 (2009).

5. Overcomming the hurdles of tumor immunity by targeting regulatory pathways in innate and adaptive immune cells. Zwirner NW, Croci DO, Domaica CI and Rabinovich GA. Curr. Pharm. Design. 16:255-267 (2010).

6. Cytokine regulation of natural killer (NK) cell effector functions. Zwirner NW and Domaica CI. Biofactors 36:274-288 (2010).

7. Nuclear factor (NF)-kB controls expression of the immunoregulatory glycan-binding protein galectin-1. Toscano MA, Campagna L, Molinero LL, Cerliani JP, Croci DO, Ilarregui JM, Fuertes MB, Nojek IM, Fededa JP, Zwirner NW, Costas MA and Rabinovich GA. Mol. Immunol. 48:1940-1949 (2011).

8. Premalignant quiescent melanocytic nevi do not express the MHC class I chain-related protein A. Fuertes MB, Rossi LE, Peralta CM, Cabrera HN, Allevato MA, and Zwirner NW. Medicina (Buenos Aires) 71:357-360 (2011).

9. Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. Rossi LE, Avila DE, Spallanzani RG, Ziblat A, Fuertes MB, Lapyckyj L, Croci DO, Rabinovich GA, Domaica CI, and Zwirner NW. J. Leukoc. Biol. 91:321-331 (2012).

10. Human Natural Killer cell maturation defect supports in vivo CD56bright to CD56dim lineage development. Domaica CI, Fuertes MB, Uriarte I, Girart MV, Sardañons J, Comas DI, Di Giovanni D, Gaillard MI, Bezrodnik L and Zwirner NW. PLoS One 7:e51677 (2012).

11. Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxiprogesterone acetate in mice bearing breast tumors restrain NK cell effector functions. Spallanzani RG, Dalotto-Moreno T, Raffo Iraolagoitia XL, Ziblat A, Domaica CI, Avila DE, Rossi LE, Fuertes MB, Battistone MA, Rabinovich GA, Salatino M and Zwirner NW. Cancer Immunol. Immunother. 12:1781-1795 (2013).

12. IL-27 stimulates human NK-cell effector functions and primes for IL-18 responsiveness. Ziblat A, Domaica CI, Spallanzani RG, Raffo Iraolagoitia XL, Rossi LE, Avila DE, Torres NI, Fuertes MB, and Zwirner NW. Eur. J. Immunol. 45:192-202 (2015).

13. Regulatory dendritic cells restrain NK cell IFN-γ production through mechanisms involving NKp46, IL-10 and MHC classI-specific inhibitory receptors. Spallanzani RG, Torres NI, Avila DE, Ziblat A, Raffo Iraolagoitia XL, Rossi LE, Domaica CI, Fuertes MB, Rabinovich GA, and Zwirner NW. J. Immunol.195:2141-2148 (2015).

14. NK cells restrain spontaneous anti-tumor CD8+ T cell priming through PD-1/PD-L1 interactions with dendritic cells. Raffo Iraolagoitia XR, Spallanzani RG, Torres NI, Araya RE, Ziblat A, Domaica CI, Sierra JM, Nuñez SY, Secchiari F, Gajewski TF, Zwirner NW, and Fuertes MB. J. Immunol. 197:953-961 (2016).

15. Expression and Functional Role of a7 Nicotinic Receptor in Human Cytokine-Stimulated NK Cells. Zanetti SR, Ziblat A, Torres NI, Zwirner NW, and Bouzat C. J. Biol. Chem. 291:16541-16552 (2016).

16. Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC. Guttlein L.N., Benedetti L.G., Fresno C., Spallanzani R.G., Mansilla S.F., Rotondaro C., Raffo Iraolagoitia X.L., Salvatierra E., Bravo A.I., Fernandez E.A., Gottifredi V., Zwirner N.W., Llera A.S., and Podhajcer O.L. Mol. Cancer. Res. 2016 Dec 28. doi: 10.1158/1541-7786.MCR-16-0243-T. [Epub ahead of print].

17. Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: the case of IL-27. Zwirner N.W., and Ziblat A. Front. Immunol. 8:25 (2017). doi: 10.3389/fimmu.2017.00025.

18. Human M2 macrophages limit NK cell effector functions through secretion of TGF-beta and engagement of CD85j. Nuñez SY, Ziblat A, Secchiari F, Torres NI, Sierra JM, Raffo Iraolagoitia XL, Araya RE, Domaica CI, Fuertes MB and Zwirner NW. J Immunol. In press (2018).

19. IL-23 stimulates IFN-gamma secretion by CD56bright NK cells and enhances IL-18-driven DC activation. Ziblat A., Nuñez S.Y., Raffo Iraolagoitia X.L., Spallanzani R.G., Torres N.I., Sierra J.M., Secchiari F., Domaica C.I., Fuertes M.B., and Zwirner N.W. Front. Immunol. (2017). In press.