Fondation MEDIC

www.fondation-medic.ch

KillerCD4 T cells: a novel candidate for human tumor immunotherapy
[24.10.2016]
Project leader – Camilla Jandus
Camilla Jandus

Camilla Jandus graduated from the Faculty of Medicine at the University of Bern in 2003, after a training at the Memorial Sloan Kettering Cancer Center in New York, and the obtaining of her MD thesis from the Institute of Pathology in Bern. From 2004 to 2008 she performed her MD-PhD training at the Ludwig Institute for Cancer Research in Lausanne, in the group of Prof P. Romero. Then, she joined for a 2-year post-doctoral training the Pharmacology Institute in Bern. In 2012, she joined as Associate Investigator the Ludwig Center for Cancer Research at the University of Lausanne. Since October 2015, supported by an Ambizione Fellowship from the Swiss National Science Foundation, she is a project leader at the Translational Tumor Immunology group at the Department of Oncology of the University of Lausanne.

Département d'oncologie fondamentale
Biopôle 3
Route de la Corniche 9A
CH-1066 Epalinges

Camilla.Jandus-Marone@unil.ch

Group members
 

Alejandra Gomez Cadena, PhD

post-doctoral fellow

Romain Loyon-Bonato, PhD

post-doctoral fellow

Sara Trabanelli, PhD

postdoctoral fellow

Amélie Cachot

PhD student

Alexander Georg Rockinger

PhD student

Bérengère Salomé

PhD student

Project description
 

Cancer immunotherapies have recently shown impressive clinical results, notably with the discovery of immune checkpoint modulators, with the development of adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) engineered cells, as well as with therapeutic vaccines. Yet, the majority of the immunotherapy strategies developed thus far have targeted tumor-specific cytotoxic CD8 T cells. Given the central role played by CD4 T cells in anti-tumor immunity, in this project we are focusing on the study of tumor-specific CD4 T cells as critical players to be exploited in future immunotherapy protocols for cancer patients.

CD4 T cells are well known for their capacity to secrete different pro- or anti-inflammatory cytokines upon antigen encounter, and for their ability to adapt their polarization to environmental stimuli. Distinct CD4 T helper and regulatory subsets have been described (e.g Th1, Th2, Th17, Th22, Treg, Tr1), and were shown to differently impact on anti-tumor immunity. In viral diseases, CD4 T cells with cytolytic functions were also identified, and in some cases their presence directly correlated with viral clearance. However, very little is known on the existence and possible relevance of tumor-specific cytotoxic CD4 T cells in human cancer. In that regard, recent reports on cancer patients receiving immune checkpoint modulators suggest that cytotoxic CD4 T cells might be crucial for efficient tumor eradication.

Recent technological advances in MHC class II epitope predictions and generation of peptide-MHC class II multimers have enabled a better characterization of human CD4 T cells, directly ex vivo or after one round of peptide in vitro stimulation.

Therefore, in this project, we will use libraries of peptide-MHC II multimers to phenotypically characterize tumor-specific cytotoxic CD4 T cells at antigen-specific level, to compare their TCR affinities to other CD4 T helper/regulatory subsets, to isolate them at the single cell level for sequencing, bioinformatics analysis and cloning, to identify stimuli able to re-polarize helper/regulatory CD4 T cells into cytotoxic cells, and vice versa, and to test their ability to kill different target cell types expressing MHC class II molecules. Finally, in vivo transfer of tumor-specific CD4 T cells harbouring different polarities, including cytotoxic ones, will allow us to test the in vivo relevance of cytotoxic CD4 T cells in terms of tumor control and translational potential.

Overall, this project will provide novel information on the molecular and phenotypic attributes of human tumor-specific cytotoxic CD4 T cells. By exploiting the panel of tumor-specific CD4 T cell clones that we will generate and characterise, TCRs specific for different tumor-associated antigenic peptides could be cloned and used to transfect and transduce CD4 and CD8 T cells for adoptive cell transfer therapy in cancer patients (TCR gene therapy using autologous lymphocytes).

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
2012 / 10.1002/ijc.26297
Baumgaertner P, Jandus C, Rivals JP, Derré L, Lövgren T, Baitsch L, Guillaume P, Luescher IF, Berthod G, Matter M, Rufer N, Michielin O, Speiser DE. Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer. 2012;130:2607-17
» PubMed