Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model

Abstract

IL-15 has potential as an immunotherapeutic agent for cancer treatment because of its ability to effectively stimulate CD8 T cell, natural killer T cell, and natural killer cell immunity. However, its effectiveness may be limited by negative immunological checkpoints that attenuate immune responses. Recently a clinical trial of IL-15 in cancer immunotherapy was initiated. Finding strategies to conquer negative regulators and enhance efficacy of IL-15 is critical and meaningful for such clinical trials. In a preclinical study, we evaluated IL-15 combined with antibodies to block negative immune regulator cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in an established murine transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostate tumor model. IL-15 treatment resulted in a significant prolongation of survival in tumor-bearing animals. Coadministration of anti-PD-L1 or anti-CTLA-4 singly with IL-15 did not improve animal survival over that of IL-15 alone. However, simultaneous administration of IL-15 with anti-CTLA-4 and anti-PD-L1 was associated with increased numbers of tumor antigen-specific tetramer-positive CD8 T cells, increased CD8 T-cell tumor lytic activity, augmented antigen-specific IFN-γ release, decreased rates of tumor growth, and improved animal survival compared with IL-15 alone. Furthermore, triple combination therapy was associated with inhibition of suppressive functions of CD4 + CD25 + regulatory T cells and CD8 + CD122 + regulatory T cells. Thus, simultaneous blockade of CTLA-4 and PD-L1 protected CD4 and/or CD8 T-cell activity from these regulatory T cells. Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.

IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

“…2). This observation was unexpected because some authors demonstrated an upregulation of PD-1 expression upon IL-15 stimulation (29,30). RLI induces a high-affinity signal through IL-15Rb/g contrary to IL-15 for which the affinity is intermediate.…”

“…As a matter of fact, a CD40 agonist, known to increase the expression of IL-15Ra on dendritic cells, has demonstrated synergistic activity in combination with IL-15 (40). In addition, IL-15 needs to be combined with both anti-CTLA-4 and anti-PD-1 ligand for tumor eradication in preclinical models (29). With this triple combination among rechallenged tumor-free animals, only 50% remained tumor free (29).…”

“…In addition, IL-15 needs to be combined with both anti-CTLA-4 and anti-PD-1 ligand for tumor eradication in preclinical models (29). With this triple combination among rechallenged tumor-free animals, only 50% remained tumor free (29).…”

A naturally occurring CD8+CD122+ T-cell subset as a memory-like Treg family

“…They demonstrated that the proliferation of CD8 1 CD122 1 Tregs in reconstituted, lymphodepleted mice limited the antitumor efficacy of DC vaccination in conjunction with adoptive transfer of tumor-specific T cells. Simultaneous inhibition of CD4 1 CD25 1 and CD8 1 CD122 1 Tregs by blocking CTLA-4 and PD-L1 protected T-cell activation from their regulation and enhanced antitumor immunity, 43 implying that CD8 1 CD122 1 Tregs hinder antitumor immunity. Taken together, CD8 1 CD122 1 Tregs regulate not only autoimmunity but also alloimmunity and tumor immunity, suggesting a broad involvement of CD8 1 CD122 1 Tregs in immune regulation.…”

Le double visage des anticorps monoclonaux en oncologie

“…Ainsi, le traitement par l'IL-15, cytokine dont on sait qu'elle stimule l'activité antitumorale des lymphocytes T CD8 + et des cellules NK et NKT, permet de prolonger la survie de souris porteuses de tumeurs de la prostate. Cet effet est observé seulement si l'IL-15 est associée à un anticorps antagoniste bloquant CTLA-4 et à un anticorps bloquant l'interaction du ligand de PD-1 (PD-L1 ou B7-H1, B7 homolog 1, CD274) -exprimé par les cellules tumorales -avec ce récepteur (➜) [16]. De plus, la fonction suppressive des lymphocytes T régulateurs CD4 + CD25 + et CD8 + CD122 + est diminuée chez les souris qui ont reçu la triple combinaison Acm/IL-15.…”