Bienvenue sur le site de l'université Paris Descartes

mai 2012

  • 04 maiT cell exhaustion in inflammatory melanoma: can it be reversed ?

    04 mai 2012

    Anne-Marie SCHMITT-VERHULST, CIML, université de Marseille, invitée par Catherine FRIDMAN à 12h.
    A germline mutation or deletion in the gene encoding the tumor suppressors p16INK4A/p14ARF is frequently observed in melanoma-prone families. Human melanoma lesions that arise in the absence of familial genetic predisposition often exhibit both loss of the tumor suppressors and activating mutations in genes in the RAS/BRAF/MAPK pathway. We developed TiRP mice in which conditional “Cre-estrogen receptor/LoxP” technology restricts the Ink4a/Arf deletion and the expression of both H-RasG12V and a natural tumor antigen (TA) to melanocytes. Melanomas developing in these mice express the neural crest marker S100, are deleted at the Ink4a/Arf locus and express transcripts for H-RasG12V as well as the cancer-germline encoded TA P1A. In this model amelanotic melanomas develop rapidly, together with the accumulation of host cells with “immunosuppressive” characteristics, including tumor infiltrating myeloid cells expressing Arginase-1 and Ptgs2/Cox2. In addition, melanoma-produced cytokines appear to induce a STAT3-dependent pro-oncogenic inflammation and inhibition of Th1-type immune responses. The TiRP melanomas are infiltrated by activated T cells lacking effector molecules such as granzyme B. These cells have an ”exhausted“ phenotype, expressing Programmed Death-1 (PD-1), an inhibitory receptor characteristic of chronically stimulated T cells, as well as many other potentially inhibitory receptors (gene array data). In view of the multiplicity of inhibitory surface receptors that appear to be expressed on melanoma-infiltrating T cells in patients, as well as in the induced melanoma in TiRP mice, we sought to design an approach to modify intracellular components in CD8 T cells to dampen the negative signaling effects rather than use extra-cellular blocking reagents to a constellation of surface molecules. To this end, we recently investigated protocols of adoptive T cell therapy which provide increased cytokine receptor signaling by intrinsic means to attempt at overcoming immunosuppression mediated by PD-1-like molecules, as well as that resulting from activation of the STAT3 and TGF-b pathways and from arginine depletion.
    Lieu : Amphithéâtre Bilski-Pasquier
    Centre de Recherche des Cordeliers
    15 rue de l’Ecole de médecine, Paris 75006