IL-15 trans-signaling with the superagonist RLI promotes effector/memory CD8+ T cell responses and enhances antitumor activity of PD-1 antagonists

Mélanie Desbois, Pauline Le Vu, Clélia Coutzac, Elie Marcheteau, Coralie Béal, Magali Terme, Alain Gey, Sébastien Morisseau, Géraldine Teppaz, Lisa Boselli, Yannick Jacques, David Béchard, Eric Tartour, Lydie Cassard, Nathalie Chaput

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    48 Citations (Scopus)

    Résumé

    Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Ra frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Ra. RLI consists of human IL-15 covalently linked to the human IL-15Ra sushi+ domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)high T cell Ig mucin-3+ CD8+ T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8+ T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8+ T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Ra/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity.

    langue originaleAnglais
    Pages (de - à)168-178
    Nombre de pages11
    journalJournal of Immunology
    Volume197
    Numéro de publication1
    Les DOIs
    étatPublié - 1 juil. 2016

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