Silencing Programmed-Death Ligands in a dendritic cell vaccine to improve tumor-reactive T cell and NK cell responses

Given their potential to stimulate both adaptive and innate anti-tumor immune responses, dendritic cells (DCs) are subject of intense examination as pharmacological tools for cancer immunotherapy. A growing body of evidence indicates that DC vaccination can be of clinical benefit to cancer patients, encouraging the further development of this therapy. Nevertheless, there is a general agreement among cancer researchers that the true clinical potential of DC-based cancer immunotherapy has not been attained yet. New DC generation protocols that boost their immunogenic properties may provide an improved clinical benefit for patients, by a more powerful activation of T cells and natural killer (NK) cells. In this context, two novel monocyte-derived DC generation protocols resulting in highly immune stimulatory DCs have been developed in vitro, focusing on (i) the use of interleukin (IL)-15 during the differentiation process (so-called IL-15 DCs, developed in the Laboratory of Experimental Hematology of the University of Antwerp), and (ii) inhibition of programmed death-1 (PD-1) activation by downregulating its ligands PD-L1 and PD-L2 with silencing RNA (developed by the collaborating group of Dolstra, Nijmegen, The Netherlands). In this project, we hypothesize that integrating PD-L silencing in our IL-15 DCs will result in superior stimulatory potential. Aiming at leveraging full force of both adaptive and innate anti-tumor immunity with DC vaccination, the objective of this study is to corroborate on the effects of PD-L silencing in IL-15 DCs regarding their T cell-specific and NK cell stimulatory potential by aggregating different established techniques. The results of these experiments will reveal the potential added value of incorporating intrinsic PD/PD-L axis blockade in our novel IL-15 DC vaccine and are likely to bring forward innovative elements that could further help optimize the clinical protocols of our DC vaccine trials.

Keywords:CANCER VACCINES, CELLULAR IMMUNE RESPONSES, IMMUNE CHECKPOINT INHIBITOR, DENDRITIC CELLS

Disciplines:Systems biology, Hematology, Immunology, Laboratory medicine, Morphological sciences, Oncology, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other clinical sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences