Checkpoint on I–O resistance: lessons learnt & future perspectives

Immune checkpoint blockade via anti-PD(L)1 has revolutionized anti-cancer treatment, with durable responses observed across multiple cancer types. However, some patients are resistant to treatment and many relapse, following initial response. Here we propose a conceptual framework aimed at promoting clearer discussion and understanding of I–O resistance. Within this framework, we define two critical factors that determine the success of anti-PD(L)1 therapy. The first is visibility of the tumor, as a foreign entity recognizable by the host’s immune system. The second is T cell functionality, as an effective means of eliminating the tumor once recognized. These two core factors are subject to modification by several different tumor cell intrinsic and extrinsic aspects of biology, which are themselves interdependent. In this perspectives article, we take each of these modifiers in turn, summarizing the field’s current state of knowledge, and considering how it can be leveraged to better direct the next generation of therapies. 

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