The IL-2 cytokine family in cancer immunotherapy

Sim, Geok Choo; Radvanyi, Laszlo G.

doi:10.1016/j.cytogfr.2014.07.018

Cited by 213 publications

(148 citation statements)

References 197 publications

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“…Its use was approved for metastatic renal cell carcinoma and melanoma. 45 However, since the finding of effects on survival of Tregs its therapeutic use is controversial, and could be counterproductive. Namely, it could lead to worsening of the disease by making tolerance to tumor antigens via Tregs rather than leading to killing of tumor cells via T killers.…”

Section: Therapeutic Optionsmentioning

confidence: 99%

Cytokines of the Immune System

Dembić

2015

The Cytokines of the Immune System

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Section: Therapeutic Optionsmentioning

confidence: 99%

Cytokines of the Immune System

Dembić

2015

The Cytokines of the Immune System

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“…For instance, IL-2 and IL-15 share the same β receptor (CD122) and are both involved in the initial amplification of antigen-specific T cell responses, and the regulation of memory T cell development, differentiation, and maintenance (30–32). In addition, both IL-2 and IL-15 induce the activation and proliferation of NK cells and enhance NK cell cytolytic activity by inducing the up-regulation of effector molecules such as perforin and granzyme B (33–35). Similarly, IL-7 and IL-15 both seem to play major, albeit non-exclusive, roles in maintaining peripheral T M homeostasis, supporting both T M proliferation and survival (31).…”

Section: Introductionmentioning

confidence: 99%

Effect of Anti–IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques

DeGottardi

Okoye

Vaidya

et al. 2016

The Journal of Immunology

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IL-15 has been implicated as a key regulator of T and NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral T and NK cell populations relative to other gamma-chain (γc) cytokines has not been fully defined in primates. Here, we address this question by determining the effect of IL-15 inhibition with a rhesusized, anti-IL-15 mAb on T and NK cell dynamics in rhesus macaques. Strikingly, anti-IL-15 treatment resulted in rapid depletion of NK cells, and both CD4+ and CD8+ effector memory T cells (TEM) in blood and tissues, with little to no effect on naïve or central memory T cells. Importantly, whereas depletion of NK cells was nearly complete and maintained as long as anti-IL-15 treatment was given, TEM depletion was countered by the onset of massive TEM proliferation, which almost completely restored circulating TEM numbers. Tissue TEM, however, remained significantly reduced, and most TEM maintained very high turnover throughout anti-IL-15 treatment. In the presence of IL-15 inhibition, TEM became increasingly more sensitive to IL-7 stimulation in vivo, and transcriptional analysis of TEM in IL-15-inhibited monkeys revealed engagement of the JAK/STAT signaling pathway, suggesting alternative γc cytokine signaling may support TEM homeostasis in the absence of IL-15. Thus, IL-15 plays a major role in peripheral maintenance of NK cells and TEM. However, whereas most NK cell populations collapse in the absence of IL-15, TEM can be maintained in the face of IL-15 inhibition by the activity of other homeostatic regulators, most likely IL-7.

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“…Altogether, we provide evidence indicating that ACLY is involved in modulating histone acetylation levels that result in induction of gene expression to promote IL-2-dependent T-cell growth. DISCUSSION IL-2-induced proliferation of T lymphocytes is vital in the generation of the immune response and a key process in current anti-cancer immunotherapy (63)(64). Nevertheless, IL-2 administration is usually accompanied by severe side effects and it is considered that a more detailed knowledge of IL-2-dependent signaling events should help improve the existing anti-cancer therapies.…”

Section: Acly Plays a Key Role In Il-2-dependent Proliferation Of Kitmentioning

confidence: 99%

Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

Osinalde

Mitxelena

Sanchez-Quiles

et al. 2016

Molecular & Cellular Proteomics

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Anti-cancer immunotherapies commonly rely on the use of interleukin-2 (IL-2) to promote the expansion of T lymphocytes. IL-2-dependent proliferation is the culmination of a complex network of phosphorylation-driven signaling events that impact on gene transcription through mechanisms that are not clearly understood. To study the role of IL-2 in the regulation of nuclear protein function we have performed an unbiased mass spectrometry-based study of the nuclear phosphoproteome of resting and IL-2-treated CD4 ؉ T lymphocytes. We detected 8521distinct phosphosites including many that are not yet reported in curated phosphorylation databases. Although most phosphorylation sites remained unaffected upon IL-2 treatment, 391 sites corresponding to 288 gene products showed robust IL-2-dependent regulation. Importantly, we show that ATP-citrate lyase (ACLY) is a key phosphoprotein effector of IL-2-mediated T-cell responses. ACLY becomes phosphorylated on serine 455 in T lymphocytes upon IL-2-driven activation of AKT, and depletion or inactivation of ACLY compromises IL-2-promoted T-cell growth. Mechanistically, we demonstrate that ACLY is required for enhancing histone acetylation levels and inducing the expression of cell cycle regulating genes in response to IL-2. Thus, the metabolic enzyme ACLY emerges as a bridge between cytokine signaling and proliferation of T lymphocytes, and may be an attractive candidate target for the development of more efficient anti-cancer The underlying principle of cancer immunotherapy is to eliminate malignant cells by tuning the immune system (1-2). This revolutionary way of fighting tumors was originated three decades ago when a patient suffering from metastatic melanoma was treated with the T-cell growth promoting factor interleukin-2 (IL-2) 1 (3). The success of IL-2 administration in fighting metastatic melanoma demonstrated for the first time that solely potentiating the activation of T lymphocytes could abrogate certain human cancers (4). Current immunotherapy approaches include the use of autologous gene-engineered T cells that, once expanded ex vivo with IL-2, are re-infused back into patients by the so-called adoptive cell transfer therapy (ACT) (5-7). Despite the promising results of this approach, a safe and long-lasting expansion of transferred T cells remains a major challenge because of the undesirable side effects derived from the use of IL-2. Continued exposure to high doses of IL-2 results in increased susceptibility of T cells to apoptosis (8). Moreover, IL-2 is also a critical component for regulatory T-cell (T reg ) development and function (9 -10), and as such it functions as a negative regulator of the immune response (11). Consequently, although IL-2 constitutes a key component of current immunotherapies, a great deal of effort is being devoted to the development of novel strategies that would boost the T-cell immune response more safely. In this regard, it has been shown that IL-2-related toxicity can be partially minimized by the use of gene-engineered T cells ex...

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The IL-2 cytokine family in cancer immunotherapy

Cited by 213 publications

References 197 publications

Cytokines of the Immune System

Cytokines of the Immune System

Effect of Anti–IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques

Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

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