Involving the innate immune system in p53-targeted combination therapies.

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells via the receptor NKG2D. For this, we will study (I) the p53 dependent induction of NKG2D ligand expression and NK cell targeting chemo- and cytokine secretion in a panel of NSCLC cell lines; (II) NK cell-mediated NSCLC tumor cell killing in co-culture experiments; and (III) the potential additional antitumor effect of interleukin 15 as potent NK cell activator. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Keywords:INNATE IMMUNITY, COMBINATION THERAPY, TARGETED THERAPY, IMMUNOTHERAPY

Disciplines:Oncology, Immunology