Local expression of interleukin‐2 by B16 melanoma cells results in decreased tumour growth and long‐term tumour dormancy

Abstract

SummaryThe tumour microenvironment is complex containing not only neoplastic cells but also a variety of host cells. The heterogeneous infiltrating immune cells include subsets of cells with opposing functions, whose activities are mediated either directly or through the cytokines they produce. Systemic delivery of cytokines such as interleukin-2 ( IL-2) has been used clinically to enhance anti-tumour responses, but these molecules are generally thought to have evolved to act locally in a paracrine fashion. In this study we examined the effect of local production of IL-2 on the growth and the immune response to B16 melanoma cells. We found that the local production of IL-2 enhances the number of interferon-c-expressing CD8 T and natural killer cells in the tumour, as well as inducing expression of vascular cell adhesion molecule 1 on tumour vessels. These responses were largely absent in interferon-c knockout mice. The expression of IL-2 in the tumour microenvironment decreases tumour growth despite also enhancing Foxp3 + CD4 + regulatory T cells and antiinflammatory cytokines such as IL-10. Higher levels of IL-2 in the tumour microenvironment eliminated the progressive growth of the B16 cells in vivo, and this inhibition was dependent on the presence of either T cells or, to a lesser extent, natural killer cells. Surprisingly however, the B16 tumours were not completely eliminated but instead were controlled for an extended period of time, suggesting that a form of tumour dormancy was established.

Melanoma dormancy in a mouse model is linked to GILZ/FOXO3A-dependent quiescence of disseminated stem-like cells

“…Additionally, Gerber et al . 56 have shown that a higher Il-2 level in the tumour microenvironment enhances the number of IFN-γ-producing CD8+ T-cells, which attenuate B16 melanoma growth and stimulate cellular dormancy. Although our results do not directly demonstrate the dependence of MeSC quiescence on CD8+ T-cells, they are consistent with this possibility.…”

Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8+ T cells

“…RNA was isolated and qRT-PCR was performed as described previously [20]. The intron-spanning forward and reverse primers used were designed in-house and obtained from Eurofins MWG Operon.…”

A novel modulation of structural and functional changes of mouse bone marrow derived dendritic cells (BMDCs) by interleukin-2(IL-2)

“…Now IL-2 has some clinical application in cancer therapy such as: as specific cellular anti-tumor immunity and cytokine induced killer (CIK) cells in cancer therapy. [18][19][20] Early documented research results in data bank have indicated that clinical significance of IL-2 to boost and maintain the balance of both innate and adaptive cellular immunity and even now IL-2 continues to be a key solution for most of melanoma and renal cancer. [21][22][23] In our current research we have proven that IL-2s affects on phenotypes and functions of BMDCs were present.…”