Abstract
BackgroundIn cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion.MethodsTwenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2.ResultsAmong the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells.ConclusionsOur results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome.
Highlights
In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome
Administration of the cytokine in the disease control rate (DCR) subgroup led to a further decrease in Foxp3+Treg cells (33.8%), which again was not statistically significant, probably because of the small number of patients involved. This would seem to indicate that combined immunological therapy, i.e. TMZ plus dendritic cell vaccination plus IL-2, at least for responding patients, effectively reduced the number of Foxp3+Treg cells, which showed a poor or null response to the growth-stimulating effect of IL-2
TMZ reduced the number of circulating Foxp3+Treg cells in all patients, including those who were treated for 7 days only
Summary
Dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. The authors of the review concluded that DC vaccination must aim to enhance antigen-specific cytotoxic T-cells and to decrease immunosuppression, perhaps through CD4+CD25++Foxp3+ regulatory T cell (Foxp3+Treg) lymphodepletion or through the use of new molecules, for example, anti-CTLA-4 or anti-PD1, or immunostimulators, e.g. CpG [4,5,6,7]. Foxp3+Tregs, a subset of CD4+ T cells, were first described by Sakaguchi [8], who discovered that these cells constitutively express high levels of interleukin-2 (IL-2) receptor α chain (CD25), preventing autoimmune diseases in mice These cells have since been shown to be involved in the development of autoimmunity, allergy, and rejection in transplant medicine and in the suppression of immune responses to cancer
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