Interleukin 21: combination strategies for cancer therapy

Abstract

In the past 20 years researchers have attempted to activate the host immune defence system to kill tumour cells and eradicate cancer. In some cases, the response of patients to immunotherapy has been extremely successful; however, other trials have shown disappointing results, and so there is a clear need for more effective therapies that can effectively adjunct conventional approaches. Interleukin 21 (IL21) is a new immune-stimulating cytokine that has demonstrated antitumour activity in several preclinical models, and has recently undergone Phase I trials in metastatic melanoma and renal cell carcinoma. Here, we provide an overview of the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.

TGF-β and tumors—an ill-fated alliance

“…Nonetheless, since TGF-β has complex and often opposing context-linked effects on its cellular targets involving TGF-β-specific pathways and crosstalk with other signal transduction pathways, will delivery of TGF-β inhibitors shift the anti-tumor response from tolerogenic to immunogenic in concert with positive effects on the tumor or will the lack of synchronous effects have disparate effects on tumorigenesis and immunogenesis [49]? More directed approaches such as eliminating Treg through Foxp3 vaccination or suppressing Foxp3 via IL-21 [20] may provide more specific and effective modes of enhancing tumor immunity [50]. From the immunologic perspective, targeting TGF-β and/ or its sources may offer respite from the ill-fated alliance between the tumor and TGF-β.…”

“…3A). IL-21 co-operates with TGF-β to induce Th17 differentiation, while suppressing Foxp3 through Stat3 and RORγt signaling [14,19] and increasing T cell resistance to Treg [20]. In this regard, in mice bearing subcutaneous HNSCC, intravenous injection of a plasmid encoding IL-21, either alone or in combination with IL-15, led to increased NK and CTL activity with significant suppression of tumor growth and increased survival [21], reflecting similar promising results in other pre-clinical tumor models and in phase I clinical trials [20].…”

L’interleukine-21, un nouvel adjuvant contre le cancer ?

“…La présence d'IL-21 favorise aussi le transfert adoptif de LTCD8 + tumoraux spécifiques dans le modèle murin de mélanome B16, retardant la croissance de la tumeur avant son élimination [6], ou dans le modèle murin de thymome EG.7 [7]. factor-a) [9]. In vivo, le traitement de souris inoculées avec des cellules cancéreuses murines surexprimant le récepteur humain HER2, avec de l'IL-21 associée à l'anticorps 4D5 (anti-HER2 humain) a permis de ralentir la croissance de la tumeur [10].…”

Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma

“…Effects of IL-21 include activation of antigen-specific CTLs, activation and differentiation of NK cells, and antibody production (Skak et al, 2008b). Furthermore, IL-21 has been shown to be an important autocrine factor of Th17 cells (Nurieva et al, 2007).…”

“…Interleukin-21 belongs to the common g-chain family, with a similarity to IL-2 and IL-21 in its sequence and structure (Asao et al, 2001). Although the effect of IL-21 on murine NK cells has been extensively elucidated (Skak et al, 2008b), there is still limited information with regard to the effect of IL-21 on human NK cells. There is a report that IL-21 enhanced human NK cytotoxicity against K562, paralleling the upregulation of perforin and granzyme (Skak et al, 2008a).…”