Intratumoral Interleukin-21 Increases Antitumor Immunity, Tumor-infiltrating CD8+ T-cell Density and Activity, and Enlarges Draining Lymph Nodes

Abstract

Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8 and CD4CD25 T cells, but not CD4CD25FoxP3 T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy of IT administration of IL-21 was due to a local rather than systemic effect. IT administration of IL-21 led to enlarged tumor-draining lymph nodes (LNs), with increased naive lymphocyte numbers and proliferation of activated lymphocytes, suggesting that local administration of IL-21 generally benefits the tumor microenvironment and activates tumor-draining LNs. Overall, our data suggest that IL-21 augments CD8 T-cell-mediated antitumor immunity through increased proliferation and effector function and acts both on tumor-infiltrating CD8 T cells as well as on the draining LNs. IT administration led to superior CD8 T-cell proliferation, effector function, and antitumor efficacy, suggesting that IT administration of IL-21 may be clinically useful in patients with unresectable tumors.

Intratumoral immunotherapy for melanoma

“…I.t. administration of IL-21 showed better treatment effect than subcutaneous injection and caused superior CD8 T cell proliferation [89]. I.t.…”

Increased expression of IL-21 reduces tumor growth by modulating the status of tumor-infiltrated lymphocytes

“…However, because of the fact that IL-21 possesses extensive immunomodulating effects, it has recently attracted attention as a tool to generate anti-tumor responses for cancer immunotherapy (di Carlo et al 2007;Sondergaard and Skak 2009;Spolski and Leonard 2008). Several reports demonstrated that administration of recombinant IL-21 (Frederiksen et al 2008;Moroz et al 2004;Sondergaard et al 2010Sondergaard et al , 2007, IL-21 gene expression vectors (Brady et al 2004;Kishida et al 2003;Wang et al 2003), or IL-21 gene-modified cells (Croce et al 2008;Dou et al 2009;Fang et al 2008;Furukawa et al 2006;Kumano et al 2007;Ugai et al 2003a,b;Zhao et al 2010) elicits significant anti-tumor responses. In addition, IL-21 also has the ability to inhibit tumor angiogenesis (Castermans et al 2008).…”

Activation of the FcgammaReceptorIIIa on human natural killer cells leads to increased expression of functional interleukin-21 receptor

“…21 In syngeneic mouse models of melanoma and renal cell carcinoma, IL-21 administered intratumorally was able to strongly inhibit tumor growth and increase the frequency of tumor-infiltrating CD8 C T cells. 42 In addition, delivery of IL-21 showed low toxicity and did not induce vascular-leak syndrome, a dose-limiting toxicity associated with other clinically utilized cytokines, such as IL-2. 43 IL-21 antitumor activities have been exploited in association with several other molecules, which showed either additive or synergistic effects.…”