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Cancer Inflammation and Immunity - Santiago Zelenay

Santiago obtained his degree in Biology from the University of Buenos Aires in 2002. As an undergraduate student he worked in DNA vaccines in the laboratory of Juan Fló. He then undertook his PhD in Immunology at the Institute Gulbenkian of Science in Portugal where he studied regulatory T cells, working with Jocelyne Demengeot and Antonio Coutinho. In 2008, he joined the group of Caetano Reis e Sousa at the CRUK London Research Institute, where he was awarded Marie Curie and EMBO long-term postdoctoral fellowships to investigate innate immune receptors and signalling pathways that trigger dendritic cell activation and drive T cell responses against viruses or tumours. In 2015, Santiago joined the CRUK Manchester Institute as a Junior Group Leader to form the Cancer Inflammation and Immunity Group, which focuses on understanding the underlying mechanisms that mediate cancer-inhibitory versus tumour-promoting inflammation in order to design new therapies for cancer patients.

In 2017, Santiago was presented with the CRUK Future Leaders in Cancer Research Prize at the NCRI Cancer Conference. This prestigious award recognises researchers who have produced research of international importance within 10 years of receiving their doctorate, and proved themselves capable of becoming leaders in the field.

Introduction

The extent to which the immune system acts as a natural barrier to cancer has been a subject of debate. This notion has recently gained great support from the clinical success of therapies aimed at exploiting cells from the immune system. Yet whether and how tumours trigger and simultaneously evade the immune system are longstanding questions in cancer biology. The Cancer Inflammation and Immunity group investigates the mechanisms underlying natural and therapy-induced tumour immunity, with a particular emphasis on identifying the cellular and molecular mediators that regulate the balance between tumour-protective versus tumour-promoting inflammation.

Inflammatory cells present at the tumour site are known for promoting several key aspects of carcinogenesis. At the same time, effective anti-tumour immunity depends on inflammatory mediators that contribute to the activation of innate immune cells such as dendritic cells. Combining the use of genetically engineered cancer models with the analysis of samples from cancer patients, our group aims to identify the underlying mechanisms that allow evasion of immune control and enable progressive tumour growth. In this context, the main objectives of the group are to elucidate the signals that trigger innate immune cell activation, initiating tumour immunity, and to   distinguish mediators that favour tumour elimination from those that support cancer progression. This distinction should allow stratification of subgroups of cancer patients with an immune promoting tumour environment likely to benefit from existing immunotherapy from those with active pathways resulting in local immune inhibition. The ultimate goal of the group is, therefore, to develop novel targeted interventions to disrupt immune suppression, promote tumour immunity and enhance the efficacy of cancer therapy.

Selected Publications


Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, Rogers NC, Sahai E, Zelenay S, Reis e Sousa C.
NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control.
Cell [ePub 8 February 2018] Article

Zelenay S*, van der Veen AG, Böttcher JP, Snelgrove KJ, Rogers N, Acton SP, Chakravarty P, Girotti MR, Marais R, Quezada SA, Sahai E, Reis e Sousa C*. (2015)
Cyclooxygenase-dependent tumor growth through evasion of immunity.
Cell 162(6):1257-70. PubMed abstract *corresponding author

Helft J, Böttcher J, Chakravarty P, Zelenay S, Huotari J, Schraml BU, Goubau D, Reis e Sousa C. (2015)
GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells.
Immunity 42(6):1197-211. PubMed abstract

Murillo MM, Zelenay S, Nye E, Castellano E, Lassailly F, Stamp G, Downward J. (2014).
RAS interaction with PI3K p110α is required for tumor-induced angiogenesis.
Journal of Clinical Investigation 124(8):3601–11. PubMed abstract

Schraml BU, van Blijswijk J, Zelenay S, Whitney PG, Filby A, Acton SE, Rogers NC, Moncaut N, Carvajal JJ, Reis e Sousa C. (2013)
Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage.
Cell 154(4):843–858. PubMed abstract

Zelenay S, Reis e Sousa C. (2013)
Adaptive immunity after cell death.
Trends in Immunology 34(7):329–335. PubMed abstract

Zelenay S, Keller AM, Whitney PG, Schraml BU, Deddouche S, Rogers NC, Schulz O, Sancho D, Reis e Sousa C. (2012)
The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice.
Journal of Clinical Investigation 122(5):1615–1627. PubMed abstract

Ahrens S, Zelenay S, Sancho D, Hanč P, Kjær S, Feest C, Fletcher G, Durkin C, Postigo A, Skehel M, Batista F, Thompson B, Way M, Reis e Sousa C, Schulz O. (2012)
F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells.
Immunity 36(4):635–645. PubMed abstract

Zelenay S*, Bergman M-L, Paiva RS, Lino AC, Martins AC, Duarte JH, Moraes Fontes MF, Bilate AM, Lafaille JJ, Demengeot J. (2010)
Cutting edge: Intrathymic differentiation of adaptive Foxp3+ regulatory T cells upon peripheral proinflammatory immunization.
Journal of Immunology 185(7):3829–3833. PubMed abstract *Corresponding author

Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, and Demengeot J. (2005)
Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion.
Proceedings of the National Academy of Sciences USA 102(11):4091–4096. PubMed abstract

Zelenay S, Elías F, Fló J. (2003)
Immunostimulatory effects of plasmid DNA and synthetic oligodeoxynucleotides.
European Journal of Immunology 33(5):1382–1392. PubMed abstract

 

Team

Postdoctoral Fellows
Eduardo Bonavita
Agrin Moeini
Victoria Pelly

Scientific Officer
Shi-Chieh Chang

Graduate Students
Eimear Flanagan
Charlotte Bell
Christian Bromley

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