Bruno Silva-Santos Lab

Immuno-Biology & Immuno-Oncology

Our research, based on Cellular and Molecular Immunology, chases fundamental questions related to the biology of white blood cells (leukocytes), such as:

• How do leukocytes develop and differentiate into immune effectors?
• What is the contribution of the various leukocyte populations to tumor progression?
• What roles do leukocytes play in tissue (patho)physiology, including upon infection?
• What are the functional implications of having leukocytes in the brain meninges?

In our Immuno-Oncology research line, we are particularly interested in T cells and macrophages, which are key players in the tumor microenvironment (TME). We study their cellular and molecular crosstalks within the TME, trying to boost anti-tumor mechanisms (based on cytotoxicity and interferon-gamma secretion) over pro-tumor effects (linked to inflammation and angiogenesis). Moreover, we have applied seminal knowledge we produced on gamma-delta (γδ) T cells onto the development of a new methodology for adoptive cell therapy of cancer – Delta One T (DOT) cells – within a spin-off company, Lymphact SA, acquired in 2018 by GammaDelta Therapeutics (London, UK). We continue to study DOT cells, their functional regulation and their molecular mechanisms of tumor cell recognition, in tight collaboration with GammaDelta Therapeutics.

In a more fundamental Immuno-Biology research line, which has been funded by the European Research Council (ERC) over the past decade, we strongly focus on gamma-delta (γδ) T cells as to better understand their differentiation and functions. Our projects range from their thymic development and effector cell differentiation, to the dissection of the functional roles in peripheral immune responses to pathogens such as Plasmodium (malaria), or their contribution to brain (patho)physiology in health (cognition) and disease (neurodegeneration).

Research Team

Research Areas

• Immuno-Oncology
• Neuroimmunology
• Lymphocyte Differentiation

Ongoing Research Projects

2021/2024: Regulation of gamma-delta T cells in the tumor microenvironment. Coordinator: Bruno Silva-Santos. Funding Agency: Fundação para a Ciência e a Tecnologia.

2021/2024: Regulating meningeal γδ17 T cell homeostasis: Molecular mechanisms and pathophysiological implications. Coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2019/2022: Next-generation CAR-DOT cells for allogeneic adoptive cancer immunotherapy. Coordinator: Bruno Silva-Santos. Funding Agency: “la Caixa” Foundation.

2018/2021: PROMISE: Programação de células mielóides anti-tumorais para aplicação em imunoterapia do cancro. Coordinator: Karine Serre. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021: Impacto das células T gd17 residentes nas meninges em funções cognitivas num contexto fisiológico e neuropatológico. Coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021: Magiciam: um sistema imunodelador de macrófagos para prevenir a invasão e metastização das células tumorais. Co-Coordinator: Karine Serre. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021: Sub-therapeutic doses of ionizing radiation modulate the pre-metastatic niche and induce metastasis. Co-Coordinator: Karine Serre. Funding Agency: Fundação para a Ciência e a Tecnologia.

2015/2021: DevoTed_miR: MicroRNA determinants of the balance between effector and regulatory T cells in vivo. Coordinator: Bruno Silva-Santos. Funding Agency: European Commission.

Awards

Our team has been distinguished with:

• Pfizer Award in Basic Research (2020), awarded to Julie Ribot and co-authors.
• Bruno Silva-Santos was elected Member of EMBO (European Molecular Biology Organization) in 2019.
• AstraZeneca Faz Ciência Award in Oncology (2019), awarded to Bruno Silva-Santos and Noella Lopes.
• Sociedade Portuguesa de Imunologia Best Paper Award 2019, awarded to Mensurado S, Rei M, Lança T, Ioannou M, Gonçalves-Sousa N, Kubo H, Malissen M, Papayannopoulos V, Serre K, Silva-Santos B.
• Prémio Janssen Inovação 2018, awarded to Sofia Mensurado, Karine Serre and Bruno Silva-Santos.
• Fundo iMM-Laço 2017 awarded to Sofia Mensurado.
• Prémio BIAL de Medicina (2017) – 2nd Prize, awarded to Bruno Silva-Santos.
• Fundo iMM-Laço 2016 awarded to Karine Serre.
• Scientific prize from Universidade de Lisboa (2016) awarded to Bruno Silva-Santos.
• Bruno Silva-Santos was nominated Honorary Member of the European Academy of Tumor Immunology in 2015.
• Bruno Silva-Santos was selected to the EMBO Young Investigator Programme (2010).
• 2nd Prize of the CESPU International Award (2010) to Julie Ribot, Ana de Barros and Bruno Silva-Santos.
• 2nd Young Investigator Award Prize of the International Cytokine Society (2009) to Bruno Silva-Santos.
• Pfizer Award in Clinical Research (2009) to Bruno Silva-Santos.
• Best Paper Award from the Portuguese Society of Immunology (2009) to Julie Ribot, Ana de Barros, Bruno Silva-Santos et al.
• 1st Post-doctoral Prize of the International Cytokine Society (2009) to Julie Ribot.

Selected Publications

Lopes N*, McIntyre C*, Martin S*, Raverdeau M*, Sumaria N, Kohlgruber A, Fiala G, Dyck L, Kellis M, Brenner M, Argüello RJ, Silva-Santos B**, Pennington DJ** and Lynch L** (2020). Distinct metabolic programs established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments. Nature Immunol: in press. (*Co-first authors; **Co-senior authors)

Ribot JC*, Lopes N* and Silva-Santos B (2020). γδ T cells in tissue physiology and surveillance. Nature Rev Immunol: in press.

Ribeiro M*, Brigas HC*, Temido-Ferreira M, Omenetti S, Stockinger B, Waisman A, Lopes LV, Silva-Santos B and Ribot JC (2019). Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory. Science Immunol 4 (40): eaay5199.

Silva-Santos B*, Mensurado S and Coffelt SB* (2019). γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nature Rev Cancer 19(7):392-404. (*Corresponding authors)

Ribot JC*, Neres R*, Zuzarte-Luís V, Gomes AQ, Mancio-Silva L, Mensurado S, Pinto-Neves D, Carvalho T, Mota MM, Silva-Santos B and Pamplona A (2019). T cells promote IFN-dependent Plasmodium pathogenesis upon liver-stage infection. Proc Natl Acad Sci U S A 116(20):9979-9988.

Caiado F, Maia-Silva D, Jardim C, Carvalho T, Simões AE, Schmolka N, Schumacher TN, Norell H and Silva-Santos B (2019). Hypomethylating agents prevent chemoresistance in acute myeloid leukemia relapses by suppressing leukemia-initiating single-cell lineages. Nature Commun 10(1): 5451.

Di Lorenzo B*, Simões AE*, Caiado F, Tieppo P, da Silva MG, Déchanet-Merville J, Schumacher TN, Prinz I, Norell H, Ravens S, Vermijlen D and Silva-Santos B (2019). Broad cytotoxic targeting of acute myeloid leukemia by polyclonal Delta One T cells. Cancer Immunol Res 7(4):552-558.

Mensurado S, Rei M, Lança T, Ioannou M, Gonçalves-Sousa N, Kubo H, Malissen M, Papayannopoulos V, Serre K, Silva-Santos B (2018). Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress. PLoS Biology 16(5):e2004990.

Schmolka N, Papotto PH, Romero PV, Amado T, Enguita FJ, Amorim A, Rodrigues AF, Gordon KE, Coroadinha AS, Boldin M, Serre K, Buck AH, Gomes AQ and Silva-Santos B (2018). MicroRNA-146a controls functional plasticity in γδ T cells by targeting Nod1. Science Immunol: 3(23): pii: eaao1392.

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

Ribeiro ST, Tesio M, Ribot JC, MacIntyre E, Barata JT and Silva-Santos B (2017). 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.

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.

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 17:721-7.

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.

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(4):992-1001.

Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Girardi M, Borst J, Hayday AC, Pennington DJ 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(4): 427-36.

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