Our group is interested in dissecting the molecular mechanisms and the regulatory networks underlying the definition of T cell identity and functional plasticity, of which we still have a limited knowledge. Indeed highly specialized T cell subsets, with different effector functions, are key to orchestrate immune responses in health and disease, thus identification of the molecular mechanisms and regulatory networks underlying T cells commitment will not only allow a better understanding of T cell functions but might also lead to the identification of novel and more specific targets to be exploited for the modulation of immune responses in the context of immune-mediated diseases (e.g. cancer and auto-immune diseases).
Our research focuses mainly on CD4+ T regulatory cells (Treg) that are physiologically engaged in the maintenance of immunological self-tolerance and immune homeostasis (Josefowicz et al., 2012; Sakaguchi et al., 2008) and are potent suppressors of effector cells. Treg cells defects have been associated to several autoimmune and inflammatory diseases. Treg cells are also found at high frequencies in various types of cancers suggesting that tumor infiltrating Treg cells contribute to the establishment of conditions that facilitate immune evasion and tumor progression through the inhibition of antitumor effector T cells activity. The idea that modulation of Treg cells within the tumor environment can lead to improved tumor therapy has been a matter of debate until recently, in the last years, though, evidence is being accumulated to support this hypothesis. Despite the encouraging results, many current therapies based on modulation of immune responses still use broad-spectrum drugs with serious side effects. Therefore the quest for highly specific and less toxic therapies is still an open challenge aimed at improving therapies efficacy and reducing unwanted adverse drug events.
To address this issue we are investigating the complexity of tumor infiltrating Treg cells (purified by human lung and colo-rectal cancer) by assessing their epigenome and transcriptome down to the single-cell level through advanced techniques based on microfluidic technologies (Fludigm C1 – Drop-sequencing). Single-cell technologies provide unprecedented opportunities to draw a more accurate picture of immune cells landscape, including their functions, basic mechanisms of response, transitions from normal to disease states and response to therapies. Our efforts are supported by a dedicated team of bioinformaticians who are working on the implementation and development of single-cell analysis pipelines.
Several recent studies including ours (Rossi et al. Nat Imm 2011 - Ranzani et al Nat Imm 2015) suggest that the definition of lymphocytes identity and the modulation of their functional plasticity is also mediated by a diverse population of non-protein-coding RNAs (ncRNAs) with regulatory potential, including microRNAs and long non-coding RNAs (lncRNAs). Long non-coding RNAs have been shown to have multiple functional facets together with a high cell-specific expression, therefore their regulation have the potential of being an important mechanism in preserving and altering lymphocyte cell phenotypes. On these premises we are investigating also the role of lncRNAs in Treg cells differentiation and function. Moreover lncRNAs cell specificity makes these molecules promising novel therapeutic targets.
• Molecular characterization of tumor infiltrating Treg cells complexity and heterogeneity
• Identification and functional characterization of long non-coding RNAs of tumor infiltrating lymphocytes as novel anti-cancer therapeutic targets.
• Establishment of immune-organoids tumor models (derived from human colo-rectal cancer) to study the interplay between tumor cells and immune cells (in particular Tregs)
Stunnenberg HG et al. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery. Cell, 167(5),1145-1149, (2016)
De Simone et al. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity, 45(5),1135-1147, (2016)
Bonnal RJ et al. miRiadne: a web tool for consistent integration of miRNA nomenclature. Nucleic Acids Res. 43(W1),W487-92, (2015)
Panzeri et al. Long intergenic noncoding RNAs: novel drivers of human lymphocyte differentiation. Front. Immunol. 6, 175 (2015)
Ranzani et al. The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4. Nat Immunol. 16(3):318-25, (2015)
Pagani et al. Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation. Immunol Rev. 253(1):82-9, (2013)
Rossi RL et al. Distinct microRNA signatures in human lymphocyte subsets and enforcement of T cell naïve state by miR-125b. Nature Immunol 12(8):796-803, (2011)
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