Interleukin-2 induces cell cycle perturbations leading to cell growth inhibition and death in malignant mesothelioma cells in vitro

Abstract

Previous report indicated that Interleukin-2 (IL-2) is able to inhibit the growth of IL-2-receptor-positive cancer cell lines without any involvement of the immune system, through IL-2-induced alterations of the cell cycle kinetics. In this study we provide evidence that IL-2 exerts anti-proliferative effect on three human malignant mesothelioma (MMe) cells in vitro, while no effects were observed on normal human mesothelial cell (HMC) primary cultures. The growth inhibitory effect of IL-2 on neoplastic cells appeared to depend on the baseline proliferative status of these cells. Indeed, in highly proliferating MMe cells, we observed a reduction of malignant cells in the S-phase of the cell cycle, with an accumulation in G0/G1, followed by apotosis for longer incubations or exposure to higher doses. On the contrary, in MMe cells proliferating at lower rate, IL-2 induces only a late cytotoxic effect, leading to apoptosis, without significantly affecting the cell cycle. IL-2Rbeta mRNA was detectable by RT-PCR in all MMe cells, IL-2Ralpha mRNA in one only out the three assayed and IL-2Rgamma mRNA in none. In addition, mRNA specific for the IL-2Rbeta-associated Jak-1 tyrosine kinase was expressed in all MMe cell lines, further suggesting that IL-2Rbeta may play a role in the observed effects. Very low, albeit detectable, levels of IL-2Rbeta chain appeared to be expressed at the cell surface of MMe cells by indirect immunofluorescence and FACS analyses. Finally, Ca(++) fluxes were rapidly induced when MMe cells were exposed to exogenous IL-2.

What's the place of immunotherapy in malignant mesothelioma treatments?

“…In the case of mesothelioma, this interleukin has also shown direct anti-proliferative effects on tumor cells in vitro. 24 Several clinical trials have been performed that are based on IL-2 injection, generally via the intrapleural route (see Table 1), but sometimes via the intravenous or subcutaneous route. The median survival for this type of treatment varies from around 8 months for patients showing tumor progression, to 13.6 months for those presenting an objective response.…”

The Role of Immunotherapy in the Treatment of Mesothelioma

“…In MM cell lines, IL-2 was shown to affect the cell cycle, resulting in an accumulation of cells in the G0/G1 phase with subsequent apoptosis (Porta et al, 2000). In the AE17 mouse model, IL-2 markedly enhanced CD8 + CTL activity and decreased tumour vasculature, resulting in tumour regression, with mice remaining tumour free for >2 months (Jackaman et al, 2003).…”

New Diagnostic and Molecular Characteristics of Malignant Mesothelioma

“…Tumor-infiltrating lymphocytes show reduced expression of activation markers and the production of cytokines is dysregulated in a murine MM model [190]. IL-12 and IL-2 have been shown to induce an anti-tumor effect in experimental models [191,192], while patient treatment with recombinant GM-CSF does not induce disease regression [193]. However, anti-tumor effect was seen with use of soluble type II TGF-b receptor and interferon-b [194,195] and interferon-g [196] in experimental models.…”