Mechanisms of cancer immunotherapy combinations

Abstract

Clinical responses to immunotherapy can be complete and sustained; however, compared to responses to conventional cancer therapies such as chemotherapy they are often delayed. It has become clear that when different cancer therapies are combined they can potentially synergize. Understanding how individual cancer therapeutics work enables the development of the most optimal combinations of cancer therapies. In this thesis, we have used interesting combinations of chemotherapy, cancer vaccines and immune checkpoint blockade and obtained insights in the mechanisms involved in these combinations. For example, we combined chemotherapy with vaccination and observed that none of the tested chemotherapeutics had a negative effect on vaccination, while only a few displayed synergy with vaccination in tumor eradication. We found that vaccine-induced T cells produce Tumor Necrosis Factor-α which could sensitize tumor cells for chemotherapy-induced cell death. Furthermore, we have shown that different cancer therapies modulate intratumoral myeloid cells in a unique manner which can critically affect the therapeutic efficacy of the therapy. Understanding how different therapies affect the local tumor environment will help to improve clinical responses and decrease toxicity in patients.