Grant: Project Grant

Why do ovarian cancer patients respond so poorly to immunotherapy? This question of key clinical relevance is hard answer, and a consensus between doctors has not been reached. The presence of immune cells in ovarian cancer is a good prognostic marker, like what is observed in other cancers where immunotherapy is instead effective. So what is the difference between these responsive and unresponsive tumors? And what can we do to make immunotherapy work better? Recently, we have focused on answering these questions, and in this application, we propose an innovative solution to change the responsiveness of ovarian cancer to immunotherapy. Our working hypothesis is that the reason why immunotherapy is not effective in ovarian cancer lies in the "poor quality" of the inflammatory environment present in the ovaries. In fact, while the presence of immune cells in the tumor bed is an important indicator that a patient will respond to immunotherapy, we must not forget that they work only under certain conditions, which are strongly dictated by the inflammatory milieu. We discovered that the ovaries are heavily populated by a population of immune cells called ILC2s, which are important mediators of immune responses against worms. Recently, a great interest has been raised by studies showing that ILC2s contribute to immune responses against cancer, but their role in ovarian cancer has not been elucidated. Considering their high inflammatory potential, we think that ILC2s can be directed to "flip" the inflammatory environment in ovarian cancer to make it more responsive to immunotherapy. In support of this hypothesis, we present exciting preliminary data that confirm that ILC2 activation synergizes with checkpoint blockade in ovarian cancer. We now propose to conduct studies to better understand how to harness these cells to make them even better effectors of anti-cancer responses and develop novel immunotherapies that could be translated in ovarian cancer patients.