Regulation of immune dysfunction in cancer

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Grégory VERDEIL
PhD
Laboratory D. Speiser

Department of oncology UNIL CHUV

Phone +41 21 692 5989
Email Gregory.verdeil@unil.ch

 

 

Research interest

Our objective is to decipher and manipulate the mechanisms that prevent tumor elimination by T cells. This is done by combining the study of human samples and animal models.

Research group projects

Identification of candidate molecular pathways causing “exhaustion” of T cells in cancer

The cancer microenvironment is highly immunosuppressive, preventing efficient elimination by the immune system and more particularly by T cells. To identify new potential regulators of the state of dysfunction (“exhaustion”) in T cells, we perform transcriptomic analysis of sorted subtypes of immune cells from melanoma in both patients and mouse models. The study of a different tumor type (bladder cancer) is also of central importance to understand the conservation of the molecular mechanisms regulating T cell dysfunction in different tumor types but also to emphasize the possible differences linked to the specificity of each cancer type. Bladder cancer is a leading cause of cancer-associated deaths in developed countries. We chose this model to perform similar analysis of “exhausted” T cells.

Manipulating mouse and human anti-tumor T cells to increase tumor elimination

In frame with the aims of the above project, we have identified several interesting target genes that regulate dysfunction in T cells. We are developing tools to manipulate the expression of these genes in both mouse and human T cells. Our aim is to improve the resistance of anti-tumor T cells to the immunosuppressive microenvironment created by the tumor and to improve their efficiency in controlling cancer.

The multiple role of MAF in immune cell regulation

Maf encodes for a transcription factor belonging to the AP-1 family. It has been studied for many years in T cells, and more specifically in CD4+ T helper (Th) differentiation. Its role in il-4 transcriptional regulation and Th2 regulation was first established using a transgenic mouse system for maf. It was also shown to play a prominent role in Th17 cells, through the regulation of il-10 and il-23r expression and Tfh cells together with the transcription factor bcl6. We recently demonstrated that maf is induced in CD4 and CD8 T cells within certain types of tumor, leading to a “dysfunctional” state of the cells. We are developing and studying mouse models to specify the role of MAF in T cells and other cell types.

Selected publications

  • Imbratta C, Leblond M, Velin D, Speiser DE, Verdeil G. MAF expression in conventional and regulatory CD4+ T cells controls gut homeostasis. 2019 Scientific Reports, Apr 16;9(1):6135. doi: 10.1038/s41598-019-42486-2
  • Smith T, Lin X, Mello M, Marquardt K, Cheung J, Lu B, Sherman LA, Verdeil G. Peripheral Deletion of CD8 T Cells Requires p38 MAPK in Cross-Presenting Dendritic Cells. J Immunol. 2017 Sep 1. pii: ji1700427. doi: 10.4049/jimmunol.170042
  • Speiser DE, Ho PC, Verdeil G, Regulatory circuits of T-cell function in cancer, Nature Reviews in Immunology, 2016 Aug 16. doi: 10.1038/nri.2016.80
  • Giordano M, Henin C,Maurizio J, Imbratta C, Bourdely P, Buferne M, Baitsch L, Vanhille L, Sieweke MH, Speiser DE, Auphan-Anezin N, Schmitt-Verhulst AM, Verdeil G; Molecular profiling of CD8 T-cells in autochthonous melanoma identifies Maf as driver of exhaustion; EMBO J. 2015 Aug 4;34(15):2042-58. doi: 10.15252/embj.201490786
  • Verdeil G, Fuertes Marraco SA, Murray T, Speiser DE ; From T cell "exhaustion" to anti-cancer immunity, BBA review for Cancer, 2015 Biochim Biophys Acta. 2015 Jun 27. doi: 10.1016/j.bbcan.2015.06.007

Funding

  • The Professor Dr Max Cloëtta Foundation
  • Swiss Cancer League
  • Swiss National Science Foundation

Group members

  • Daniella CROPP
    PhD student
     
  • Emma DESPONDS
    Master student
     
  • Nicolas GESTERMANN
    Laboratory manager
     
  • Marine LEBLOND
    Postdoctoral fellow
     
  • Laure TILLÉ
    PhD student
Ch. des Boveresses 155 - CH-1066 Epalinges
Switzerland
Tel. +41 21 692 59 92
Fax +41 21 692 59 95
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