High-dimensional single cell analysis of the T cell immune response
Affiliation: Humanitas Research Hospital, department of Immunology, via Manzoni 56, 20089, Rozzano, Milan, Italy
Enrico Lugli is group leader and head of facility at Humanitas Research Hospital, where he leads the Translational Immunology Lab and the Flow Citometry core facility.
Lugli obtained his PhD in Immunology from the University of Modena and Reggio Emilia, Italy, under the supervision of Prof. Andrea Cossarizza, where he studied T cell immune responses and homeostasis in Human Immunodeficiency Virus (HIV) infection. He then moved to the Vaccine Research Center at the National Institutes of Health in Bethesda, MD, USA, to join the ImmunoTechnology Section directed by Dr. Mario Roederer, where in collaboration with Nicholas Restifo, identified stem-like memory T cells, thus defining a novel paradigm for the development of more effective adoptive cell transfer immunotherapies.
In collaboration with Dr. Thomas Waldmann, he moved Interleukin (IL)-15, a cytokine capable of activating anti-tumor effector cells, from the preclinical stage to the first-in-human phase I clinical trial in patients with solid cancers. After a brief period as a senior scientist under the supervision of Prof. Domenico Mavilio, he became group leader at Humanitas Research Hospital, where he studies how T cell responses mediate human tumor regression and how these are hindered by the presence of immunosuppressive populations, especially CD4+ regulatory T cells (Treg).
Lugli’s research has been funded by a Starting Grant from the European Research Council, the Lloyd J. Old STAR award from the Cancer Research Institute, the Italian Association for Cancer Research (Fondazione AIRC) and by the Italian Ministry of Health.
Stem-like memory T cell differentiation in cancer immunotherapy.
Following our original studies on the identification of T stem cell memory cells (Gattinoni, Lugli et al., Nat Med, 2011; Lugli, et al., J Clin Invest, 2013), we were the first to show that a subset with enhanced functionality and stem-like properties exists among PD-1+ exhausted T cells in human tumors (Brummelman et al., J Exp Med, 2018). More recently, by using omics technologies, we have redefined the model of memory T cell differentiation in humans by reporting the existence of two subsets of stem-like T cell progenitors with parallel differentiation programs and distinct fate commitments, functional vs. dysfunctional (Galletti et al., Nature Immunol, 2020). Once acquired, these traits of dysfunction cannot be reverted: they are “hard-wired” to the differentiation program. Our major question is now to define the niche of stem-like subsets in tumor tissues to understand how stromal, tumoral and immune cells regulate their differentiation and function.
Immunosuppression in the tumor microenvironment
The landscape of immune cells infiltrating tumors is highly complex. We recently identified unprecedented cellular players mediating immunosuppression and driving disease progression in several human cancers’ microenvironment. We found that the differentiation and function of a subset of highly suppressive effector regulatory T (Treg) cells is governed by the expression of two key transcription factors: interferon regulatory factor 4, IRF4 (Alvisi et al., J Clin Invest, 2020), and mesenchyme homeobox-1, MEOX-1 (MEOX-1; Alvisi et al., J Hepatol, 2022). A major question is how Tregs sustain chronic activation and resist exhaustion and senescence. We will address this by using novel sequencing and proteomic technologies applied to primary patients’ samples.
- Alvisi G, Termanini A, Soldani C, Portale F, Carriero R, Pilipow K, Costa G, Polidoro M, Franceschini B, Malenica I, Puccio S, Lise V, Galletti G, Zanon V, Colombo FS, De Simone G, Tufano M, Aghemo A, Di Tommaso L, Peano C, Cibella J, Iannacone M, Roychoudhuri R, Manzo T, Donadon M, Torzilli G, Kunderfranco P, Di Mitri D, Lugli E, and Lleo A. Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target. J Hepatol. 2022 Jun 20;S0168-8278(22)00370-1.
- Zehn D, Thimme R, Lugli E, de Almeida GP, and Oxenius A. ‘Stem-like’ precursors are the fount to sustain persistent CD8(+) T cell responses. Nat Immunol. 2022 Jun;23(6):836-847.
- Galletti G, De Simone G, Mazza EMC, Puccio S, Mezzanotte C, Bi TM, Davydov AN, Metsger M, Scamardella E, Alvisi G, De Paoli F, Zanon V, Scarpa A, Camisa B, Colombo FS, Anselmo A, Peano C, Polletti S, Mavilio D, Gattinoni L, Boi SK, Youngblood BA, Jones RE, Baird DM, Gostick E, Llewellyn-Lacey S, Ladell K, Price DA, Chudakov DM, Newell EW, Casucci M, and Lugli E. Two subsets of stem-like CD8(+) memory T cell progenitors with distinct fate commitments in humans. Nat Immunol. 2020. Dec;21(12):1552-1562.
- Pilipow, K., Scamardella, E., Puccio, S., Gautam, S., De Paoli, F., Mazza, E. M., De Simone, G., Polletti, S., Buccilli, M., Zanon, V., Di Lucia, P., Iannacone, M., Gattinoni, L. & Lugli, E. Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity. JCI insight 2018 Sep 20;3(18):e122299.
- Brummelman, J., Mazza, E. M. C., Alvisi, G., Colombo, F. S., Grilli, A., Mikulak, J., Mavilio, D., Alloisio, M., Ferrari, F., Lopci, E., Novellis, P., Veronesi, G. & Lugli, E. High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors. J Exp. Med. 2018 Oct 1;215(10):2520-2535.