U.O. name

Immunoregulation

Scientific Coordinator

Prof. Lorenzo Moretta

Description

This Operative Unit studies the role of Natural Killer (NK) cells in physiological and pathological conditions. It is mainly involved in translational studies in the field of tumor immunology, with particular focus on the interactions involving tumor cells, tumor microenvironment and immune cells. A major topic is represented by the characterization of NK cells, the main effectors of innate immunity against tumors. Over the years this Unit has largely contributed to pivotal studies regarding the differentiation and the functional characterization of these cells.

More recently, the interactions of NK cells with tumor cells and stromal cells in the tumor microenvironment have been more deeply investigated in order to better understand the mechanisms by which cancer cells can escape the immune response. A major goal is to identify novel therapeutic strategies based on the activation not only of NK cells but also of other immune cells (i.e. gamma/delta T lymphocytes, effector T cells).

These studies may therefore have an important clinical relevance by providing useful information for understanding the effects of current anti-cancer therapies and for the design of novel therapeutic approaches.

Research activity of the Operative Unit includes the following research areas:

  • Differentiation and characterization of Innate Lymphoid Cells (ILC);
  • Analysis of cellular and molecular interactions involving NK cells, tumor cells and components of the tumor microenvironment;
  • Immunobiology of solid tumors (tumor models: melanoma, lung and renal carcinomas);
  • Characterization of NK cells infiltrating the decidua during early pregnancy and of the interaction between NK cells and decidual stromal cells.

List of publications

  1. Carrega P, Loiacono F, Di Carlo E, Scaramuccia A, Mora M, Conte R, Benelli R, Spaggiari GM, Cantoni C, Campana S, Bonaccorsi I, Morandi B, Truini M, Mingari MC, Moretta L, Ferlazzo G. NCR(+)ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat Commun. 2015 Sep 23;6:8280. doi: 10.1038/ncomms9280. PMID: 26395069
  2. Ambrosini P, Loiacono F, Conte R, Moretta L, Vitale C, Mingari MC. IL-1β inhibits ILC3 while favoring NK-cell maturation of umbilical cord blood CD34(+) precursors. Eur J Immunol. 2015 Jul;45(7):2061-71. doi: 10.1002/eji.201445326. Epub 2015 May 12. Erratum in: Eur J Immunol. 2015 Aug;45(8):2420. PMID: 25847448ì
  3. Vacca P, Montaldo E, Croxatto D, Loiacono F, Canegallo F, Venturini PL, Moretta L, Mingari MC. Identification of diverse innate lymphoid cells in human decidua. Mucosal Immunol. 2015 Mar;8(2):254-64. doi: 10.1038/mi.2014.63. Epub 2014 Jul 23. PMID: 25052762
  4. Grauwet K, Vitale M, De Pelsmaeker S, Jacob T, Laval K, Moretta L, Parodi M, Parolini S, Cantoni C, Favoreel HW. Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a. J Virol. 2015 Nov 18;90(3):1522-33. doi: 10.1128/JVI.02902-15. PMID: 26581992
  5. Hasmim M, Bruno S, Azzi S, Gallerne C, Michel JG, Chiabotto G, Lecoz V, Romei C, Spaggiari GM, Pezzolo A, Pistoia V, Angevin E, Gad S, Ferlicot S, Messai Y, Kieda C, Clay D, Sabatini F, Escudier B, Camussi G, Eid P, Azzarone B, Chouaib S. Isolation and characterization of renal cancer stem cells from patient-derived xenografts. Oncotarget. 2015 Nov 2. doi: 10.18632/oncotarget.6266. [Epub ahead of print] PMID: 26551931
  6. Montaldo E, Teixeira-Alves LG, Glatzer T, Durek P, Stervbo U, Hamann W, Babic M, Paclik D, Stölzel K, Gröne J, Lozza L, Juelke K, Matzmohr N, Loiacono F, Petronelli F, Huntington ND, Moretta L, Mingari MC, Romagnani C. Human RORγt(+)CD34(+) cells are lineage-specified progenitors of group 3 RORγt(+) innate lymphoid cells. Immunity. 2014 Dec 18;41(6):988-1000. doi: 10.1016/j.immuni.2014.11.010. Epub 2014 Nov 28. PMID: 25500367
  7. Grauwet K, Cantoni C, Parodi M, De Maria A, Devriendt B, Pende D, Moretta L, Vitale M, Favoreel HW.Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1-dependent NK cell-mediated lysis of infected cells. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16118-23. doi: 10.1073/pnas.1409485111. Epub 2014 Oct 28. PMID: 25352670
  8. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol. 2014 Jun;44(6):1582-92. doi: 10.1002/eji.201344272. Review. PMID: 24777896
  9. Carrega P, Bonaccorsi I, Di Carlo E, Morandi B, Paul P, Rizzello V, Cipollone G, Navarra G, Mingari MC, Moretta L, Ferlazzo G. CD56(bright)perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph. J Immunol. 2014 Apr 15;192(8):3805-15. doi: 10.4049/jimmunol.1301889. Epub 2014 Mar 19. PMID: 24646734
  10. Vacca P, Martini S, Mingari MC, Moretta L. NK cells from malignant pleural effusions are potent antitumor effectors: A clue for adoptive immunotherapy? Oncoimmunology. 2013 Apr 1;2(4):e23638. PMID: 23734317
  11. Spaggiari GM, Moretta L. Cellular and molecular interactions of mesenchymal stem cells in innate immunity. Immunol Cell Biol. 2013 Jan;91(1):27-31. doi: 10.1038/icb.2012.62. Epub 2012 Nov 13. Review. PMID: 23146943
  12. Balsamo M, Manzini C, Pietra G, Raggi F, Blengio F, Mingari MC, Varesio L, Moretta L, Bosco MC, Vitale M. Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur J Immunol. 2013 Oct;43(10):2756-64. doi: 10.1002/eji.201343448. Epub 2013 Aug 5. PMID: 23913266
  13. Montaldo E, Vitale C, Cottalasso F, Conte R, Glatzer T, Ambrosini P, Moretta L, Mingari MC. Human NK cells at early stages of differentiation produce CXCL8 and express CD161 molecule that functions as an activating receptor. Blood. 2012 Apr 26;119(17):3987-96. doi: 10.1182/blood-2011-09-379693. Epub 2012 Mar 7. PMID: 22403260
  14. Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A, Balsamo M, Conte R, Benelli R, Minghelli S, Solari N, Gualco M, Queirolo P, Moretta L, Mingari MC. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res. 2012 Mar 15;72(6):1407-15. doi: 10.1158/0008-5472.CAN-11-2544. Epub 2012 Jan 18. PMID: 22258454
  15. Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, Fulcheri E, Darretta V, Moretta L, Mingari MC. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2402-7. doi: 10.1073/pnas.1016257108. Epub 2011 Jan 19. PMID: 21248224
  16. Vacca P, Moretta L, Moretta A, Mingari MC. Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol. 2011 Nov;32(11):517-23. doi: 10.1016/j.it.2011.06.013. Epub 2011 Aug 31. PMID: 21889405
  17. Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, Fenoglio D, Ragni N, Moretta L, Mingari MC. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11918-23. doi: 10.1073/pnas.1001749107. Epub 2010 Jun 14. PMID: 20547831
  18. Bonaccorsi I, Cantoni C, Carrega P, Oliveri D, Lui G, Conte R, Navarra M, Cavaliere R, Traggiai E, Gattorno M, Martini A, Mingari MC, Moretta A, Ferlazzo G. The immune inhibitory receptor LAIR-1 is highly expressed by plasmacytoid dendritic cells and acts complementary with NKp44 to control IFNα production. PLoS One. 2010 Nov 30;5(11):e15080. doi: 10.1371/journal.pone.0015080. PMID: 21151495
  19. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M, Queirolo P, Vermi W, Facchetti F, Moretta A, Moretta L, Mingari MC, Vitale M. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20847-52. doi: 10.1073/pnas.0906481106. Epub 2009 Nov 23. PMID: 19934056
  20. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood. 2009 Jun 25;113(26):6576-83. doi: 10.1182/blood-2009-02-203943. Epub 2009 Apr 27. PMID: 19398717

Main research lines

1. Study of the “Innate Lymphoid Cells” (ILC):

  1. Characterization of physiological and pathological mechanisms involved in the differentiation of human innate lymphocytes belonging to the family of ILC;
  2. Phenotypical and functional analyses of different ILC subpopulations under physiological (ILC derived from decidua and from endometrial tissues) and pathological conditions (ILC isolated from pleural effusions derived from patients affected by different types of tumors);
  3. Study of the interactions between ILC and stromal cells, neutrophils, and myeloid cells.

2. Study of the molecular mechanisms involved in the interactions between tumor cells and the immune system during neoplastic progression:

  1. Analysis of the effects mediated by components of the tumor microenvironment (tumor cells, cancer stem cells, immune cells and stromal cells) on the effector functions of NK cells;
  2. Role of tumor microenvironment on the modulation of NK cell differentiation starting from CD34+ haematopoietic precursors;
  3. Molecular characterization of ligands recognized by activating NK receptors involved in NK cell-mediated cytotoxic activity;
  4. Proteomic approaches for the characterization/identification of membrane proteins expressed by tumor cells and for surface proteome profiling.

3. Assessment of the effects of innovative anti-tumor therapies on the immune response:

  1. Study of the effects mediated by BRAF and MEK inhibitors on immune cell functions; influence of the immune response conditioned by these drugs in the control of tumor growth (melanoma);
  2. Evaluation of immunological status in patients with non-small cell lung carcinoma (NSCLC) undergoing immunotherapy with monoclonal antibodies specific for “checkpoint inhibitors” (anti PD-1/anti PDL-1).

Research group ERC sector

LS6 Immunity and infection, LS6_1 Innate immunity

Internal personnel

Surname Name Department Title Scientific area
Moretta Lorenzo DIMES Full professor MED 04
Mingari Maria Cristina DIMES Full professor MED 04
Cantoni Claudia DIMES Full professor MED 04
Spaggiari Maria Grazia DIMES Researcher MED 04

Other personnel

  • Gabriella Pietra, Ricercatore confermato, DIMES
  • Grazia Maria Spaggiari, Ricercatore confermato, DIMES
  • Paola Vacca, Ricercatore Tempo Determinato, DIMES
  • Chiara Vitale, Ricercatore confermato, DIMES

Collaborations

  • Dott.ssa Paola Queirolo - UO Oncologia Medica A e coordinatore DMT melanomi e tumori cutanei IRCCS San Martino-IST, Genova
  • Dott.ssa Marina Gualco - UO Anatomia Patologica IRCCS San Martino-IST, Genova
  • Dott.ssa Simona Zupo - S.S. Diagnostica Molecolare IRCCS San Martino-IST, Genova
  • Dott.ssa Daniela Detotero - UO Patologia molecolare IRCCS San Martino-IST, Genova
  • Dott. Massimo Vitale - UO Immunologia /Sez. Microambietnte Tumorale e immunità innata IRCCS San Martino-IST, Genova
  • Dott. Filippo Ballerini - UO Clinica Ematologica/degenza IRCCS San Martino-IST, Genova
  • Dott.ssa Alessandra Bo - UO Servizio Trasfusionale/Banca del sangue cordonale IRCCS San Martino-IST, Genova
  • Prof. Andrea De Maria - DISSAL, Università di Genova/IRCSS AOU San Martino-IST, Genova
  • Prof.ssa Cinzia Domenicotti/Dott.ssa Barbara Marengo - DIMES-Sez. Patologia Generale, Università di Genova
  • Prof.ssa Bianca Sparatore - DIMES, Università di Genova
  • Dott. Luigi Varesio/Dott.ssa Maria Carla Bosco - Istituto G Gaslini, Genova
  • Dott. Giuseppe Morreale - Istituto G. Gaslini, Genova
  • Dott. Vincenzo Tarantino - UOC di Otorinolaringoiatria - Istituto G. Gaslini, Genova Dott. Giuseppe Cervo - UOC di Cardiochirurgia e Chirurgia Vascolare- Istituto G. Gaslini, Genova
  • Dott. Andrea Petretto - Lab. Core Facilities, Istituto G. Gaslini, Genova
  • Dott. Giovanni Candiano - Lab. Nefrologia, Istituto G. Gaslini, Genova
  • Prof. Bruno Azzarone - Istituto G. Gaslini, Genova
  • Prof. Franco Locatelli, Dott.ssa Francesca Moretta - Ospedale Bambino Gesù, Roma
  • Prof Dieli/Caccamo - Università di Palermo
  • Prof. Guido Ferlazzo - Università di Messina
  • Prof.ssa Silvia Deaglio - Università di Torino
  • Prof. Giovanni Camussi - Università di Torino
  • Prof. AG Brooks/Dr. LC Sullivan - University of Melbourne, Australia
  • Dott.ssa Chiara Romagnani - Deutsches Rheuma Forschungszentrum Berlin, Germany
  • Prof. Herman Favoreel - University of Ghent, Belgium
  • Prof. Eric Vivier - CIML, Marseille, France