Fondation MEDIC

www.fondation-medic.ch

Harnessing T cells for cancer immunotherapy: Modulation of the mTOR signaling pathway to fine tune CD8+ T cell differentiation
[19.10.2016]
Project leader – Pedro Romero
Pedro Romero

Dr. Pedro Romero obtained his MD at the School of Medicine of the National University of Colombia in Bogota. Then he performed experimental work in the field of immunology of malaria and participated in the development of malaria vaccines, initially at the Institute of Immunology, Faculty of Medicine, National University of Colombia in Bogota and then as a postdoctoral fellow at the Department of Medical and Molecular Parasitology, New York University School of Medicine. He joined the Lausanne branch of the Ludwig Institute for Cancer Research in 1989.
He is currently a Member of the Ludwig Center for Cancer Research and is the head of the Translational Tumor Immunology Group at the Ludwig Center and the Associate director of the Department of Fundamental Oncology. He was appointed Professor at the Faculty of Biology and Medicine of the University of Lausanne in 2003 and was named Ordinary Professor January 2011. He has been actively involved in pre-clinical and translational research in tumor immunology and immunotherapy. His main interests focus on the study of tumor antigens, human T cell responses and development of immunotherapy of cancer.

Ludwig Center for Cancer Research
Department of Fundamental Oncology
Faculty of Biology and Medicine
University of Lausanne

E-Mail: pedro.romero@unil.ch

Laboratory web page

Group members
 

Alena Donda PhD

Research associate

Lianjun Zhang PhD

Postdoctoral fellow

Nina Dumauthioz

Doctoral student

Project description
 

CD8 T cells are key effectors of protective anti-tumor immunity. The goal of current efforts to develop immune system-based therapies for cancer aims at raising strong tumor antigen-specific CD8 T cell responses. It becomes therefore essential to understand the molecular events underlying the processes of CD8 T cell proliferation, differentiation and survival in order to better inform therapeutic immune interventions.
We focus on investigating the role of microRNA-155 (miR-155) for cytolytic CD8 T cell responses. Initially, we found that miR-155 is strongly upregulated upon human (1) and mouse (2) T cell activation. Using mice deficient for miR-155, we then established an important role for miR-155 in accumulation of antigen specific CD8 T cells during in vivo response to either acute viral infection or vaccination with synthetic peptides and TLR agonists.

figure 1

More specifically, effector T cell accumulation to the lymphochoriomeningitis virus (LCMV) infection was strongly diminished, and the anti-tumor response upon peptide vaccination was inefficient when T cells were lacking miR-155. Conversely, we also observed that the anti-tumor response could be dramatically enhanced by overexpression of miR-155 in tumor antigen specific CD8 T lymphocytes. Surprisingly, whereas miR-155 deficient T cells were drastically reduced in numbers, their differentiation by acquisition of effector functions remained intact. Furthermore, we detected a defect in formation of classical memory T cell phenotypes. Importantly, we could show that the reason for impaired effector T cell accumulation was cell-intrinsic. Downregulation of SOCS-1, which among other molecules is a validated target of miR-155 in CD4 T cells, may be a mechanism for the observed effects in CD8 T cells.

Further experiments challenging SOCS-1 transgenic mice with LCMV virus revealed that SOCS-1 overexpression could indeed mimic the effects observed in the miR-155 deficient mice.

SOCS-1 suppresses cytokine signaling by de-phosphorylation of STAT5. Indeed, the levels of pSTAT5 were strongly reduced in response to the common γ-chain cytokines IL-2, IL-7 and IL-15 in naïve and effector miR-155 deficient CD8 T cells. This suggested higher SOCS-1 levels in miR-155 cells as a mechanism for impaired cytokine signaling. In fact, we detected reduced proliferation and increased apoptosis in virus-specific, miR-155 deficient CD8 T cells, suggesting that both mechanisms contributed to the impaired accumulation of effector cells and maybe the consequence of blunted γ-chain cytokine signaling. Importantly, preliminary data show rescue of cytokine responsiveness in miR-155 deficient CD8 T cells by lentiviral suppression of SOCS-1. Moreover, wild type cells with experimentally suppressed SOCS-1 levels accumulated to higher levels and were much more potent in anti-tumor responses (2). Finally, we found that the impaired memory T cell formation was at least in part due to strongly affected CD4 helper generation and diminished serum cytokine levels during LCMV infection. In summary, we identified the miR-155/SOCS-1 pathway as central for activation of virus- and tumor-specific cytolytic T cells. Our ongoing work will now focus on further understanding the role of miR-155 for efficient effector and memory T cell generation in order to identify ways to increase miR-155 levels in T cells for efficient therapy of cancer.

Publications
 
2016 / 10.1038/ncomms10554
Ludigs K, Jandus C, Utzschneider DT, Staehli F, Bessoles S, Dang AT, Rota G, Castro W, Zehn D, Vivier E, Held W, Romero P, Guarda G. NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions. Nat Commun. 2016 7:10554
» PubMed
2016 / 10.1016/j.ebiom.2016.01.019
Scholz G, Jandus C, Zhang L, Grandclément C, Lopez-Mejia IC, Soneson C, Delorenzi M, Fajas L, Held W, Dormond O, Romero P. Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells. EBioMedicine. 2016;4:50-61
» PubMed
2015 / 10.1080/2162402X.2015.1029702
Chevalier MF, Bobisse S, Costa-Nunes C, Cesson V, Jichlinski P, Speiser DE, Harari A, Coukos G, Romero P, Nardelli-Haefliger D, Jandus C, Derré L. High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools. Oncoimmunology. 2015;4: e1029702
» PubMed
2014 / 10.1172/JCI65899
Jandus C, Boligan KF, Chijioke O, Liu H, Dahlhaus M, Démoulins T, Schneider C, Wehrli M, Hunger RE, Baerlocher GM, Simon HU, Romero P, Münz C, von Gunten S. Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance. J Clin Invest. 2014;124:1810-20
» PubMed
2013 / 10.1172/JCI65325
Hebeisen M, Baitsch L, Presotto D, Baumgaertner P, Romero P, Michielin O, Speiser DE, Rufer N. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J Clin Invest. 2013 Mar;123(3):1044-56
» PubMed
2013 / 10.1016/j.immuni.2012.12.006
Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, Merck E, Boudousquie C, Utzschneider DT, Escobar TM, Perret R, Muljo SA, Hebeisen M, Rufer N, Zehn D, Donda A, Restifo NP, Held W, Gattinoni L, Romero P. MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity. 2013 Apr 18;38(4):742-53
» PubMed
2013
Salaun B, Dudda JC, Ji Y, Palmer DC, Merck E, Boudousquie C, Utzschneider DT, Escobar TM, Perret R, Muljo SA, Zehn D, Donda A, Restifo NP, Held W, Gattinoni L, Romero P. MicroRNA-155 and its target SOCS-1 shape the effector CD8 T cell response to virus and cancer. Manuscript submitted
» PubMed
2012 / 10.1074/jbc.M111.337154
Fayyad-Kazan H, Rouas R, Fayyad-Kazan M, Badran R, El Zein N, Lewalle P, Najar M, Hamade E, Jebbawi F, Merimi M, Romero P, Burny A, Badran B, Martiat P. MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of differentially expressed microRNAs on expression of two genes essential to their function. J Biol Chem. 2012 Mar 23;287(13):9910-22
» PubMed
2011 / 10.1186/1479-5876-9-44
Salaun B, Yamamoto T, Badran B, Tsunetsugu-Yokota Y, Roux A, Baitsch L, Rouas R, Fayyad-Kazan H, Baumgaertner P, Devevre E, Ramesh A, Braun M, Speiser D, Autran B, Martiat P, Appay V, Romero P. Differentiation associated regulation of microRNA expression in vivo in human CD8+ T cell subsets. J Transl Med. 2011 Apr 20;9:44
» PubMed
2010 / 10.1074/jbc.M110.119628
Fayyad-Kazan H, Rouas R, Merimi M, El Zein N, Lewalle P, Jebbawi F, Mourtada M, Badran H, Ezzeddine M, Salaun B, Romero P, Burny A, Martiat P, Badran B. Valproate treatment of human cord blood CD4-positive effector T cells confers on them the molecular profile (microRNA signature and FOXP3 expression) of natural regulatory CD4-positive cells through inhibition of histone deacetylase. J Biol Chem. 2010 Jul 2;285(27):20481-91
» PubMed
2009 / 10.1002/eji.200838509
Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothé F, Simion A, Akl H, Mourtada M, El Rifai M, Burny A, Romero P, Martiat P, Badran B. Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 2009 Jun;39(6):1608-18
» PubMed