Dr. Michele Ardolino

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Dr. Michele Ardolino
Assistant Professor, Department of Biochemistry, Microbiology and Immunology

501 Smyth Road, Cancer Center Room 3-328

Office: 613-737-8899 ext. 77257
Lab: 613-737-8899 ext. 77253

Work E-mail: m.ardolino@uottawa.ca

Dr. Michele Ardolino

Biography

As a young student, I have always been fascinated by the complexity of nature and I found myself amazed when I have started studying the immune system and its unique combination of elegance and efficacy. For this reason, once I completed my master in Biotechnology, I enthusiastically joined the Immunological Science program at the University of Rome as a graduate student. In the laboratory directed by Angela Santoni, I have studied how two populations of immune cells, T cells and NK cells, interact with each other in the human system. As most of my academic education took place in Italy, I decided to move to the US for my post-doctoral training, and in 2010 I joined the group of David Raulet at the University of California, Berkeley. In David’s lab, I have investigated the mechanisms that underlie the failure of the immune response to tumors. My time in Berkeley was precious and I received an excellent training in tumor immunology. I published several high profile papers and I became an expert in the immuno-oncology field. In 2016, I was recruited by a joint effort of the University of Ottawa and the Ottawa Hospital Research Institute to lead a group in cancer immunology. My laboratory is interested in understanding the complex interactions between immune cells and tumors to find new ways to harness the immune system against cancer.

Research Interests

The immune system is an incredible weapon against tumors and yet, cancer is still one of the leading causes of death. It is of extreme importance to have a more detailed knowledge of the complex interactions between immune cells and cancer in order to design more tailored and effective immunotherapies. My group is interested in understanding why a subset of immune cells named Natural Killer (NK) cells are often unable to kill tumor cells and to find new ways to harness the activity of NK cells against cancer.

Research Activities

The function of Natural Killer (NK) cells is embedded in their name: they should kill! Then why do NK cells often fail to respond to tumors?

This question has been at the very center of my research since 2010, and despite some answers were found, there are still many open questions.

My group at OHRI and uOttawa is interested in deciphering the molecular pathways and the cellular interactions that lead to failure of NK cell response to tumors. We use this knowledge to design tailored immunotherapies to mobilize NK cells against cancer.

Currently the lab is focusing on:

  1.  determining the functions of checkpoint receptors on NK cells: we discovered that the checkpoint receptor PD-1 is expressed and powerfully inhibit NK cell responses to tumors (Ardolino et al., under revision). We are now interested in understanding the role of other members of the checkpoint receptor family on NK cells, both in mouse models and taking advantage of human specimens.
  2. understanding the cellular networks that suppress the NK cell response to cancer: the tumor microenvironment is extraordinarily complex: tumor cells, immunoregulatory cells and effector cells, not to mention stromal cells, interact with each other in a dynamic network that often lead to the generation of an immunosuppressive environment. Understanding the cellular interactions that suppress NK cells in the tumor bed represents an important step towards finding an effective way of mobilizing NK cell responses against cancer.
  3. deciphering the molecular pathways responsible for suppressing NK cell activation in the tumor microenvironment: NK cell activation is finely regulated by a balance of signals deriving from activating and inhibitory receptors expressed on their surface. Very little is known about the intracellular signalling that negatively tunes the NK cell responses. By using a reductionist approach, as well as an unbiased genetic screening, we aim to find new pathways that reduce the ability of NK cells to respond to tumor cells.

 

Dr. Ardolino is currently looking for a Research Technician to work in his laboratory at the OHRI. If you are interested, please send your complete CV with cover letter and a description of research experience to: mardolino@ohri.ca.

 

Selected Top Publications

Shifrin N., Kissiov D.U.*,  Ardolino M.*, Joncker N., Raulet D.H. Dissociation of tolerance and hyporesponsiveness of NK cells and differential roles of host cell types in imposing hyporesponsiveness. The Journal of Immunology, 2016, 15; 197(10): 4127-4136 *Equal contribition

Iannello A., Thompson T.W., Ardolino M., Lowe S.W., Raulet D.H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. The Journal of Experimental Medicine, 2013, 210 (10); 2057-69

Ardolino M., Zingoni A., Cerboni C., Cecere F., Soriani A., Iannitto M.L., Santoni A. DNAM-1 ligands expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T-cell interaction. Blood, 2011, 117 (18); 4778-86

Ardolino M., Azimi C.S., Iannello A., Trevino T.N., Horan L., Zhang L., Deng W., Ring A. Fischer S., Garcia K.C., Raulet D.H. Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. The Journal of Clinical Investigation, 2014, 124 (11):4781-94

All other Publications

Ardolino M., Hsu J., Azimi C.S., Trevino T.N., Iannello A., Raulet D.H. The checkpoint regulator PD-1 inhibits NK cell responses to tumors. Manuscript in review, Nature, 2016

Spiegel A., Houshyar S., Brooks M., Reinhardt F., Ardolino M., Fessler E., DeCock J., Zervantonakis I. K., Ng Eaton E., Iwamoto Y., Cortez-Retamozo V., Pittet M. K., Raulet D. H., Weinberg R.A. Neutrophils suppress intraluminal NK tumor cell clearance and enhance extravasation. Cancer Discovery, 2016, 6(6): 630-49

Ardolino M., Raulet D.H. Cytokine therapy restores anti-tumor responses of NK cells rendered anergic in MHC I-deficient tumors. Oncoimmunology, 2016, 5(1): e1002725

Iannello A., Thompson T.W., Ardolino M., Marcus A., Raulet D.H. Immunosurveillance of tumors by innate immune cells. Current Opinion in Immunology, 2016, 38: 52-8

Ardolino M., Hsu J., Raulet D.H. Cytokine treatment in cancer immunotherapy. Oncotarget, 2015, 14; 6(23): 1936-7

Shifrin N., Raulet D.H., Ardolino M. NK cell tolerance, responsiveness and missing self recognition. Seminars in Immunology, 2014, 26 (2):138-44

Marcus A., Gowen B.G., Thompson T., Iannello A., Ardolino M., Deng W., Wang L., Shifrin., Raulet D.H. Recognition of tumors by the innate immune system and natural killer cells. Advances in Immunology, 2014, 122:91-128

Bekerman E., Jeon D., Ardolino M., Coscoy L. A role for host activation-induced cytidine deaminase in innate immune defense against KSHV. Plos Pathogens, 2013, 9 (11); e1003748

Sheppard S., Triulzi C., Ardolino M., Serna D., Raulet D.H., Guerra N. Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire. Blood, 2013, 121 (25); 5025-33

Zingoni A., Ardolino M., Santoni S., Cerboni C. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Frontiers in Immunology, 2013, 3; 408

Zingoni A., Cerboni C., Ardolino M., Santoni A. Modulation of T-cell mediated immune responses by Natural Killer cells (Chapter 17). in J. Zimmer (Ed): Natural Killer Cells, at the forefront of modern immunology. Springer, 2010

Cerboni C., Ardolino M., Santoni A, Zingoni A. Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells. Blood, 2009, 113; 2955-64

 

Fields of Interest

  • Immunology
  • Innate immunity
  • NK cells
  • tumor immunology
  • immuno-oncology
  • Immunotherapy
  • checkpoint blockade
  • PD-1
  • Microbiology
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