Innate like and CD4+ T Cells in Cancer

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Olivier Lantz Team Leader Tel:

Our group studies in vivo T cell biology in mouse and human models.

We are focusing on three main topics:

1) Study of the mucosal associated invariant T (MAIT) cells: an evolutionarily conserved T cell selected by MHC-related protein I (MR1) on gut B cells. MAIT cells are the most abundant innate like T cells in humans where they represent 1-8 and 20-40 % of blood and liver T cells, respectively.

We have discovered a T cell sub population whose specificity is conserved between species characterized by the use of an invariant chain, the Vα7.2/19-Jα33 TCRα chain. These cells are localized in the gut lamina propria and require the presence of B cells in the same location both in humans and in mice. These T cells are called Mucosal associate invariant T cells (MAIT) and are selected by the MHC related molecule 1, MR1 which is also highly conserved between species.

We showed that MAIT cells development is a stepwise process with an intra-thymic MR1 dependent but B cell and commensal flora independent selection process followed by a peripheral maturation and expansion requiring B cells and the commensal flora.

MAIT cells are activated and secrete Interferon-g after stimulation by fibroblasts or antigne presenting cells co-cultured with bacteria and yeasts but not viruses. MAIT cells migrate to the site of bacterial infection both in humans and mice. They display protective function in 2 models of infectious disease. Expression of the multidrug-receptor transporter would explain the ability of MAIT cells to resist the xenobiotics secreted by bacteria while the capacity to secrete IL-17 would fit with their anti-bacterial activity.

We have developed a new mouse model harboring a high number of MAIT cells that are also fluorescent by introgressing both a wild mouse gene and a ror(gt) GFP transgene. This will allow us to study how MAIT cells are protective against specific infections.

2) Study of the interactions between tumors expressing nominal antigens in a constitutive or inducible way and specific T cells

Growth of "spontaneous" lung tumors expressing a nominal antigen leading to the proliferation of specific T cells in the draining mediastinal lymph-node Mice harboring an inducible constitutively active K-Ras received a virus coding for a luciferase, the antigen and a Cre recombinase intra-tracheally. Tumors appear as light emitting mass in the lund. Specific Marilyn CD4 T cells recognizing the tumor antigen were injected at week 23 and analysis was carried out 3 weeks later.
Growth of “spontaneous” lung tumors expressing a nominal antigen leading to the proliferation of specific T cells in the draining mediastinal lymph-node
Mice harboring an inducible constitutively active K-Ras received a virus coding for a luciferase, the antigen and a Cre recombinase intra-tracheally. Tumors appear as light emitting mass in the lund. Specific Marilyn CD4 T cells recognizing the tumor antigen were injected at week 23 and analysis was carried out 3 weeks later.

Our goal is to better understand the relationship between tumors expressing a nominal antigen at a given time and location, and a minimal immune system specific for that same antigen. Using transplantable tumor models expressing antigen in an inducible manner or spontaneous tumor models expressing nominal antigens, we try to decipher whether the tumor is ignored or leads to deletion, anergy or class switch of the specific immune response or generate suppressor T cells.

The models have been implemented (Figure) and the immune response is being analyzed. These same models are used to develop new anti-cancer vaccines based on long peptide or DNA vaccination targeting the antigen to antigen presenting cells. Treatments associating vaccinations and chemotherapy are also tested.

3) Study of the immune response during the treatment of cancer patients.

We show that the CD4 T cells are aware of the tumor since the early stages since an increased number of CD4 T cells displaying signs of chronic activation are found in the blood of patients harboring small tumors. We are now analysing the specificity of these cells.

 

Key publications

Year of publication 2020

Partula V1,2, Deschasaux M1, Druesne-Pecollo N1, Latino-Martel P1, Desmetz E1, Chazelas E1, Kesse-Guyot E1, Julia C1,3, Fezeu LK1, Galan P1, Hercberg S1,3, Mondot S4, Lantz O5,6, Quintana-Murci L7, Albert ML8, Duffy D9; Milieu Intérieur Consortium, Srour B1, Touvier M1. (2020 May 5)

Associations between consumption of dietary fibers and the risk of cardiovascular diseases, cancers, type 2 diabetes, and mortality in the prospective NutriNet-Santé cohort.

The American Journal of Clinical Nutrition : DOI : 10.1093/ajcn/nqaa063
Lynn GM1,2, Sedlik C3,4, Baharom F5, Zhu Y6, Ramirez-Valdez RA5, Coble VL6, Tobin K5, Nichols SR6, Itzkowitz Y6, Zaidi N5, Gammon JM7, Blobel NJ5, Denizeau J3,4, de la Rochere P3,4, Francica BJ8,9, Decker B6, Maciejewski M6, Cheung J5, Yamane H5, Smelkinson MG10, Francica JR5, Laga R11, Bernstock JD6,12, Seymour LW13, Drake CG8,14, Jewell CM7, Lantz O3,4, Piaggio E3,4, Ishizuka AS5,6, Seder RA15. (2020 Mar 2)

Peptide-TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens.

Nat Biotechnol. : 38(3) : 320-332 : DOI : 10.1038/s41587-019-0390-x

Year of publication 2019

Salou M, Lantz O. (2019 Nov 1)

A TCR-Dependent Tissue Repair Potential of MAIT Cells.

Trends in immunology : 40(11) : 975-977 : DOI : 10.1016/j.it.2019.09.001
Scepanovic P, Hodel F, Mondot S, Partula V, Byrd A, Hammer C, Alanio C, Bergstedt J, Patin E, Touvier M, Lantz O, Albert ML, Duffy D, Quintana-Murci L, Fellay J; Milieu Intérieur Consortium. (2019 Sep 13)

xA comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals.

: 13;7(1) : 130 : DOI : 10.1186/s40168-019-0747-x
François Legoux, Déborah Bellet, Celine Daviaud, Yara El Morr, Aurelie Darbois, Kristina Niort, Emanuele Procopio, Marion Salou, Jules Gilet, Bernhard Ryffel, Aurélie Balvay, Anne Foussier, Manal Sarkis, Ahmed El Marjou, Frederic Schmidt, Sylvie Rabot, Olivier Lantz (2019 Aug 31)

Microbial metabolites control the thymic development of mucosal-associated invariant T cells.

Science (New York, N.Y.) : DOI : eaaw2719
François Legoux, Jules Gilet, Emanuele Procopio, Klara Echasserieau, Karine Bernardeau, Olivier Lantz (2019 Aug 22)

Molecular mechanisms of lineage decisions in metabolite-specific T cells.

Nature immunology : 1244-1255 : DOI : 10.1038/s41590-019-0465-3
All publications