Insufficient Th1 polarisation blocks RCC vaccine efficacy

By Laura Cowen, medwireNews Reporter

A lack of a clinical response to an allogenic gene-modified renal cell cancer (RCC) vaccine may be due to insufficient type 1 T-helper cell (Th1) polarisation, show results of a gene expression profiling study.

The study was carried out by Anne Flörcken (Charité University Medicine, Berlin, Germany) and colleagues to establish why RCC patients enrolled in a phase I clinical did not respond clinically when vaccinated with a human leucocyte antigen-A2-matched RCC cell line transfected with interleukin (IL)-7 and CD80.

The researchers found that, compared with healthy controls, the expression of a variety of immunologically relevant genes were “profoundly reduced” in peripheral blood mononuclear cells (PBMCs) collected from the nine RCC patients prior to vaccination, indicating that “impaired immunological responsiveness is a baseline characteristic in RCC patients”, they remark.

When the genes were grouped according to cellular processes, the team observed downregulation of those encoding dendritic cell maturation, suggesting impaired antigen presentation, as well those implicated in the immediate early immune response.

Vaccination resulted in partial reversal of this downregulation, as well as upregulation of genes encoding cytotoxic T lymphocyte and natural killer cell responses, “clearly demonstrating [vaccine-induced] immune activation”, say the authors.

In accordance with these findings, gene signatures indicating impaired T cell cytokine responses, IL-2 signalling and activation and interferon (IFN) signalling responses at baseline were partially restored after vaccination.

No significant changes were observed in IL-12 expression, but the IL-10 pathway, which was downregulated at baseline, was strongly upregulated upon vaccination.

Flörcken and team also observed significant baseline downregulation of various NF-κB gene expression signatures, important for triggering an innate and adaptive immune response, that were upregulated following vaccination.

This led them to develop an in vitro model for vaccine-induced immune responses that allowed analysis of the effects of NF-κB inhibition. Healthy PBMCs incubated with the vaccine showed a Th1 polarised immune response with predominant vaccine-induced secretion of IL-2, IFN-γ and TNF-α. There was no IL-12 release upon stimulation with the vaccine, but IL-10 secretion was detected.

However, cytokine secretion was suppressed in the presence of the NF-κB inhibitor MLN120B.

These results “show that stimulation with the vaccine leads to a (partially) TH-1-polarized immune response, but both the lack of IL-12 secretion and secretion of IL-10 may explain insufficient TH-1-polarization/[cytotoxic T lymphocyte]-induction in vivo”, the researchers write in the International Journal of Cancer.

They hypothesise that tumour-induced NF-κB is a major mechanism in both the immunosuppression of RCC patients and the lack of Th1 polarisation after vaccination.

“Whether this is primarily due to profound immunosuppression caused by a large tumor burden in our patients or rather reflects insufficient immunostimulatory properties of the vaccine itself, remains to be clarified”, they conclude.

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