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Silva-Santos, Bruno
Lab

T cell Differentiation & Tumor Targeting

T lymphocytes play crucial roles in cellular immunity against pathogens and tumors. However, T lymphocytes can also be a major cause of autoimmunity and allergy. These (patho)physiological roles of T lymphocytes depend on their cellular and molecular activities, namely the production of cytotoxic molecules and pro- versus anti-inflammatory cytokines. In our Lab we employ in vitro and in vivo models to study the differentiation, activation and expansion (in response to infections or tumors) of murine and human T lymphocytes.

We have previously demonstrated that the development of important T lymphocyte subsets, namely gamma-delta (γδ) T cells and regulatory T cells, is orchestrated by molecular events taking place in the thymus that are highly dependent on interactions between the receptor CD27 (expressed on T cell progenitors) and its ligand CD70 (mostly present on thymic epithelial cells). Moreover, the CD27/CD70 signaling pathway is also critical for the expansion of γδ T cells in the periphery, which may be exploited in future cancer immunotherapy protocols. In this context, we have also identified novel molecular determinants of tumor cell recognition by human gamma-delta T cells, which unexpectedly are based on natural killer (NK) receptors such as NKG2D or NKp30. In the future we plan to further dissect the molecular pathways that control γδ T cell activation and tumor cell recognition. Most importantly, we aim to apply our knowledge on γδ T cells to the pre-clinical and clinical targeting of acute and chronic leukemias. Given that the major therapeutic hurdle following conventional chemotherapy consists of leukemia relapse, we will explore the possibility of using immune intervention (based on γδ T cells) to target escape variants and thus prevent cancer relapse.

  • Research Areas

    T cell differentiation and activation

    • Role of costimulatory receptors and cytokines
    • Epigenetic and transcriptional regulation
    • MicroRNA-mediated regulation

    Tumor immunology

    • Tumor cell dynamics and clonal evolution: impact on immune evasion
    • Tumor cell recognition via NK receptors
    • Tumor-promoting leukocyte subsets
  • Research Team

    • Ongoing Research Projects

      • 2010-2015 European Research Council, Starting Grant, Project 260352: Differentiation of pro-inflammatory T cell subsets in vivo
      • 2014-2015 Fundação para a Ciência e Tecnologia, EXPL/IMI-IMU/0170/2013: Characterization of the molecular mechanisms of differentiation of the human γδ T cell lymphocytes
      • 2014-2015 Fundação para a Ciência e Tecnologia, EXPL/BIM-ONC/1656/2013: Quantitative analysis of clonal evolution and characterization of the escape variants on Acute Myeloyd Leukemia relapse
      • 2014/2016 Associação Portuguesa Conta a Leucemia, "Preprogrammed versus stochastic clonal evolution of relapsing Acute Myeloid Leukemia: Impact on disease development and therapeutic responses".
    • Prizes

      Our team has been distinguished with:

      • Pfizer Award in Clinical Research (2009) to B. Silva-Santos;
      • Best Paper Award from the Portuguese Society of Immunology (2009) to J. Ribot, A. deBarros, B. Silva-Santos et al.;
      • 1st Post-doctoral Prize of the International Cytokine Society (2009) to J. Ribot;
      • 2nd Young Investigator Award Prize of the International Cytokine Society (2009) to B. Silva-Santos;
      • 2nd Prize of the CESPU International Award (2010) to J. Ribot, A. deBarros and B. Silva-Santos.
      • B. Silva-Santos was also selected to the Young Investigator Programme of the European Molecular Biology Organization (2010); and nominated to the Editorial Boards of OncoImmunology (2011), European Journal of Immunology (2012) and Immunity, Infection and Disease (2013).
    • Selected Publications

      • Papotto PH*, Ribot JC* and Silva-Santos B (2017). IL-17+ γδ T cells as kick-starters of inflammation. Nature Immunol: 18(6):604-611. Review.

      • Muñoz-Ruiz M, Sumaria N, Pennington DJ and Silva-Santos B (2017). Thymic determinants of γδ T cell differentiation. Trends Immunol 38(5):336-244. Review

      • Ribeiro ST, Tesio M, Ribot JC, MacIntyre E, Barata JT and Silva-Santos B (2016). Casein kinase 2 controls the survival of normal thymic and leukemic γδ T cells via promotion of AKT signaling. Leukemia Dec 16, doi: 10.1038/leu.2016.363.

      • Muñoz-Ruiz M, Ribot JC, Grosso AR, Gonçalves-Sousa N, Pamplona A, Pennington DJ, Regueiro JR, Fernandez-Malavé E and Silva-Santos B (2016). TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets. Nature Immunol 17(6):721-7.

      • Almeida AA, Correia DV, da Silva CL, da Silva MG, Anjos DR and Silva-Santos B (2016). Delta One T cells for immunotherapy of chronic lymphocytic leukemia: clinical-grade expansion/ differentiation and preclinical proof-of-concept. Clin Cancer Res 22(23):5795-5804.

      • Barros-Martins J, Schmolka N, Fontinha D, Simas JP, Brok I, Ferreira C, Veldhoen M, Silva-Santos B and Serre K (2016). Effector γδ T cell differentiation relies on master but not auxiliary Th cell transcription factors. J Immunol 196(9):3642-52. 

      • Silva-Santos B, Serre K and Norell H (2015). γδ T cells in cancer. Nature Rev Immunol 15(11):683-91. Review.

      • Schmolka S, Wencker M, Hayday AC and Silva-Santos B (2015). Epigenetic and transcriptional regulation of γδ T cell differentiation: programming cells for responses in time and space. Seminars Immunol pii: S1044-5323(15)00003-2. Review.

      • Rei M, Gonçalves-Sousa N, Lança T, Thompson RG, Mensurado S, Balkwill FR, Kulbe H, Pennington DJ and Silva-Santos B (2014). Murine CD27(-) Vγ6(+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages. Proc Natl Acad Sci U S A 111(34):E3562-70

      • Schmolka N*, Serre K*, Grosso AR, Rei M, Pennington DJ, Gomes AQ and Silva-Santos B (2013). Epigenetic and transcriptional signatures of stable versus plastic differentiation of pro-inflammatory γδ T cell subsets. Nature Immunol 14(10): 1093-100. (*Equal contributions)
      • Coquet J*, Ribot JC*, Babala N, Middendorp S, Xiao Y, Neves JF, Fonseca-Pereira D, Jacobs H, Pennington DJ, Silva-Santos B** and Borst J** (2013). Epithelial and dendritic cells in the thymic medulla promote CD4+ Foxp3+ regulatory T cell development via the CD27-CD70 pathway. Journal of Experimental Medicine 210(4):715-28 (*,**Equal contributions)
      • Lança T, Souza MF, Gonçalves-Sousa N, Rei M, Grosso AR, Penido C and Silva-Santos B (2013). Protective role of the inflammatory CCR2/ CCL2 chemokine pathway through recruitment of type 1 cytotoxic γδ T lymphocytes to tumor beds. J Immunol 190(12): 6673-80.
      • Hudspeth K, Fogli M, Correia D, Mikulak J, Roberto A, Della Bella S, Silva-Santos B* and Mavilio D* (2012). Engagement of NKp30 on Vδ1+ T-cells induces the production of CCL3, CCL4 and CCL5 and suppresses HIV-1 replication. Blood 119(17): 4013-6. (*Equal contributions)
      • Ribot JC, deBarros A, Mâncio-Silva L, Pamplona A and Silva-Santos B (2012). B7-CD28 costimulatory signals control the survival and proliferation of murine and human γδ T cells via interleukin-2 production. J Immunol 189(3): 1202-8.
      • Correia DV, Fogli M, Hudspeth K, da Silva MG, Mavilio D* and Silva-Santos B* (2011). Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118: 992-1001
      • Mahtani-Patching J, Neves JF, Pang DJ, Stoenchev KV, Aguirre-Blanco AM, Silva-Santos B and Pennington DJ (2011). PreTCR and TCRγδ signal initiation in thymocyte progenitors does not require domains implicated in receptor oligomerization. Science Signal 4: ra47.
      • Lança T., Correia D. V., Moita C. F., Raquel H., Ferreira C., Ramalho J. S., Barata J. T., Moita L. F., Gomes A. Q. and Silva-Santos B. (2010). The MHC class Ib protein ULBP1 is a non-redundant determinant of leukemia/ lymphoma susceptibility to γδ T-cell cytotoxicity. Blood: 115(12): 2407-11.
      • Ribot J. C., Chaves-Ferreira M., d'Orey F., Wencker M., Gonçalves-Sousa N., Decalf J., Simas J. P., Hayday A. C. and Silva-Santos B. (2010). Cutting Edge: Adaptive versus innate signals selectively control the pool sizes of IFN-γ- or IL-17-producing γδ T cells upon infection. J Immunol: 185(11):6421-5.
      • Gomes A. Q.*, Correia D. V.*, Grosso A. R., Lança T., Ferreira C., Lacerda J. F., Barata J. T., Gomes da Silva M. and Silva-Santos B. (2010). Identification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood γδ T cells. Haematologica: 95(8):1397-404. (*Equal contributions)
      • Gonçalves-Sousa N, Ribot JC, deBarros A, Correia DV, Caramalho I and Silva-Santos B (2010). Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T-cells is cell-contact dependent and sensitive to GITR modulation. Eur J Immunol 40(1): 61-70.
      • Ribot J. C., deBarros A., Pang D. J., Neves J. F., Peperzak V., Girardi M., Borst J., Hayday A. C., Pennington D. J. and Silva-Santos B. (2009) CD27 is a thymic determinant of the balance between IFN-γ- and IL-17-producing γδ T cell subsets. Nature Immunol 10: 427-436.

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