TY - JOUR
T1 - IL-15 trans-signaling with the superagonist RLI promotes effector/memory CD8+ T cell responses and enhances antitumor activity of PD-1 antagonists
AU - Desbois, Mélanie
AU - Vu, Pauline Le
AU - Coutzac, Clélia
AU - Marcheteau, Elie
AU - Béal, Coralie
AU - Terme, Magali
AU - Gey, Alain
AU - Morisseau, Sébastien
AU - Teppaz, Géraldine
AU - Boselli, Lisa
AU - Jacques, Yannick
AU - Béchard, David
AU - Tartour, Eric
AU - Cassard, Lydie
AU - Chaput, Nathalie
N1 - Publisher Copyright:
© Copyright 2016 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84975299077&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1600019
DO - 10.4049/jimmunol.1600019
M3 - Article
C2 - 27217584
AN - SCOPUS:84975299077
SN - 0022-1767
VL - 197
SP - 168
EP - 178
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -