Genomics of the innate immune system

Group Leader

Renato Ostuni

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We are a multidisciplinary group that combines high-throughput and single-cell genomics, bioinformatics, genome engineering and functional studies to dissect principles of immune cell development and functions. Building on relevant mouse models and uniquely available clinical samples, we aim to decipher the complex networks of signaling pathways, transcription factors, chromatin regulators and non-coding RNAs that control gene expression in the innate immune system.

We are constantly looking for energetic and enthusiastic individuals at all career stages. Unsolicited applications are welcome and for more information contact Renato Ostuni.

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Research activity

Our research focuses on two areas:

Homeostatic and stress-induced development of the human innate immune system. In this project, the group uses cutting-edge genomics and single-cell transcriptomics technologies to explore stress-induced human myelopoiesis in sets of clinical samples collected longitudinally throughout allogeneic hematopoietic stem cell (HSC) and BM transplantation procedures. This research will uncover the cellular and molecular mechanisms of immune reconstitutions after chemotherapy, with direct implications for HSC gene therapy and treatment of hematological malignancies.

Transcriptional control of macrophage activation in pancreatic cancer. The group aims to dissect how macrophage functions are affected by complex combination of environmental stimuli during homeostasis and disease, with a focus on cancer. Tumor-associated macrophages (TAM) frequently display a “mixed” polarization state characterized by concomitant pro- and anti- inflammatory activities that support, rather than suppress, tumor growth. In the lab, the aim is to define the phenotype and functions of TAM, and to develop innovative cell and gene therapy strategies to therapeutically reprogram macrophage activities.

Selected publications

Alexandre P. Bénéchet; Giorgia De Simone; Pietro Di Lucia; Francesco Cilenti; Giulia Barbiera; Nina Le Bert; Valeria Fumagalli; Eleonora Lusito; Federica Moalli; Valentina Bianchessi; Francesco Andreata; Paola Zordan; Elisa Bono; Leonardo Giustini; Weldy V. Bonilla; Camille Bleriot; Kamini Kunasegaran; Gloria Gonzalez-Aseguinolaza; Daniel D. Pinschewer; Patrick T. F. Kennedy; Luigi Naldini; Mirela Kuka; Florent Ginhoux; Alessio Cantore; Antonio Bertoletti; Renato Ostuni*; Luca G. Guidotti*; Matteo Iannacone* Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming Nature. 2019 Oct;574(7777):200-205. *co-last author

Natoli G*, Ostuni R* Adaptation and memory in immune responses. Nat Immunol. 2019 Jul;20(7):783-792. *Co-corresponding author

Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, Barcella M, Spinelli O, Greco R, Crucitti L, Cieri N, Noviello M, Manfredi F, Montaldo E, Ostuni R, Naldini MM, Gentner B, Waterhouse M, Zeiser R, Finke J, Hanoun M, Beelen DW, Gojo I, Luznik L, Onozawa M, Teshima T, Devillier R, Blaise D, Halkes CJM, Griffioen M, Carrabba MG, Bernardi M, Peccatori J, Barlassina C, Stupka E, Lazarevic D, Tonon G, Rambaldi A, Cittaro D, Bonini C, Fleischhauer K, Ciceri F, Vago L. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med. 2019 Apr;25(4):603-611.

Ng LG*, Ostuni R*, Hidalgo A. Heterogeneity of neutrophils, Nat Rev Immunol. 2019 Apr;19(4):255-265. *Co-corresponding author

Escobar G, Barbarossa L, Barbiera G, Norelli M, Genua M, Ranghetti A, Plati T, Camisa B, Brombin C, Cittaro D, Annoni A, Bondanza A, Ostuni R, Gentner B, Naldini L. Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens. Nat Commun. 2018 Jul 24;9(1):2896.

Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, Traversari C, Bordignon C, Ciceri F, Ostuni R, Bonini C, Casucci M, Bondanza A. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018 Jun;24(6):739-748.

Piccolo V, Curina A, Genua M, Ghisletti S, Simonatto M, Sabò A, Amati B, Ostuni R*, Natoli G*. Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk. Nature Immunology 2017 May;18(5):530-540. *Co-last and corresponding author.

Sammicheli S, Kuka M, Di Lucia P, de Oya NJ, De Giovanni M, Fioravanti J, Cristofani C, Maganuco CG, Fallet B, Ganzer L, Sironi L, Mainetti M, Ostuni R, Larimore K, Greenberg PD, de la Torre JC, Guidotti LG, Iannacone M. Inflammatory monocytes hinder antiviral B cell responses. Science Immunology 2016 Oct 21;1(4). pii: eaah6789.

Ostuni R*, Natoli G, Cassatella MA, Tamassia N*. Epigenetic regulation of neutrophil development and function. Seminars in Immunology 2016 Apr;28(2):83-93. *Co-last and corresponding author.

Ostuni R*, Kratochvill F, Murray PJ, Natoli G*. Macrophages and cancer: from mechanisms to therapeutic implications. Trends in Immunology. 2015 Apr;36(4):229-39. *Co-corresponding author.

Ostuni R*, Natoli G*. Lineages, cell types and functional states: a genomic view. Curr Opin Cell Biol. 2013 Dec;25(6):759-64. *Co-corresponding author

Ostuni R*, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G*. Latent enhancers activated by stimulation in differentiated cells. Cell 2013 Jan 17;152(1-2):157-71. Highlights in Nature Reviews Genetics, Nature Immunology, F1000 (13 stars). *Co-corresponding author.

Zanoni I*, Ostuni R*, Barresi S, Di Gioia M, Broggi A, Costa B, Marzi R, Granucci F. CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice. Journal of Clinical Investigations 2012 May;122(5):1747-57.*Co-first author.

Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell. 2011 Nov 11;147(4):868-80. Highlights in F1000 (2 stars).

Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi AE, Rocchetti M, Mingozzi F, Foti M, Chirico G, Costa B, Zaza A, Ricciardi-Castagnoli P, Granucci F. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature. 2009 Jul 9;460(7252):264-8. Highlights in F1000 (2 stars).