Mechanisms of resistance to immune checkpoint inhibitors

Abstract

The emergence of immune checkpoint inhibitors in recent years has transformed cancer treatment in many tumor types. Durable clinical responses in refractory cancer types have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. In addition, some of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance is a result of complex and constantly evolving interactions between cancer cells and the immune system. Some mechanisms of resistance have been characterized to date, and more continue to be uncovered. The tumor microenvironment, tumor immunogenicity, and oncologic pathways play roles in response and resistance to immune checkpoint blockade. By elucidating and targeting mechanisms of resistance, treatments can be guided to improve clinical outcomes. Combination treatment strategies with immune checkpoint inhibitors are being tested in clinical trials, with several already in clinical use. This review will discuss the different resistance mechanisms and potential therapeutic strategies to overcome resistance.