Development of immune checkpoint therapy for cancer

Abstract

Since the early 20th century, immunologists have investigated mechanisms that protect vertebrates from damaging immune responses against self-antigens by mature lymphocytes, i.e., peripheral tolerance. These mechanisms have been increasingly delineated at the molecular level, ultimately culminating in new therapeutics that have revolutionized clinical oncology. Here, we describe basic science and clinical discoveries that converge mainly on two molecules, CTLA-4 and PD-1, that were recognized with the 2018 Nobel Prize in Physiology or Medicine awarded to James Allison and Tasuku Honjo. We discuss their investigations and those of many others in the field that contravene tolerance through checkpoint inhibition to boost immune killing of malignant cells. We also discuss the mechanisms underlying each therapy, the efficacy achieved, and the complications of therapy. Finally, we hint at research questions for the future that could widen the success of cancer immunotherapy.

Figure 1.

Mechanisms of CTLA-4 function and inhibition. (A–C) CTLA-4 is up-regulated on activated T cells and inhibits further T cell activation by competing with CD28 for B7 ligation. T reg cells, which constitutively express CTLA-4, trans-endocytose B7 ligands on APCs to prevent CD28 costimulation. (D) Blocking CTLA-4 results in enhanced CD28-B7 ligation, which unleashes T cell expansion and effector function. By inhibiting CTLA-4 on T reg cells, B7 trans-endocytosis is suppressed, resulting in increased APC potency. CTLA-4 blockade is also thought to cause T reg cell depletion through ADCC by cells expressing Fcγ receptors.

Figure 2.

Mechanisms of PD-1 function and inhibition. (A and B) PD-1 is expressed by activated T cells and binds to PD-L1 and PD-L2 on APCs or other nonimmune cells to inhibit T cell signaling through a poorly defined mechanism. Chronic T cell signaling results in exhaustion and an inability to properly function. (C) PD-1/PD-L1 inhibition unleashes the expansion of CD4⁺ and CD8⁺ T cell populations, resulting in increased memory formation and cytotoxic T cell responses.