PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?

Abstract

PD-1-PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1-PD-L1 axis is affected by the complex immunologic regulation network, and some CD8⁺ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.

Keywords: MSI; PD-1; PD-L1; TMB; biomarker; combination immunotherapy; immune checkpoint blockade; resistance mechanism.

Figure 1

Schematic illustration of PD-1/PD-L1 expression in the tumor setting as a marker of T cell activation and driver of T cell dysfunction, as well as a predictive biomarker for response to PD-1/PD-L1 blockade in PD-L1⁻ and PD-L1⁺ tumors according to the prevailing notion. PD-L2, which is infrequently expressed and potentially has PD-1-independent positive function, is not depicted in the figure for clarity. The PD-L1–CD80 axis is also not illustrated because its role and significance in the cancer setting is unclear. (A) In tumors (or tumor clones) with cell-intrinsic PD-L1 expression driven by the oncogenic pathways, whether anti-PD-1/PD-L1 is effective may depend on the activity of the PD-1–PD-L1 axis. If T-cell infiltration is lacking (a “desert”-like immune landscape, or “cold” tumors), or PD-1 is not expressed on T cells, anti-PD-1 therapy will not elicit a de novo T cell response. If the tumor is infiltrated with immune cells (“hot” tumor) and the oncogenic or immunogenic PD-L1 expression suppresses T cell activation by binding to PD-1 within the T-cell receptor microclusters, anti-PD-1/PD-L1 therapy can be effective. IDO1, NO (nitric oxide), and suppressive cytokines in the tumor microenvironment may contribute to resistance to PD-1/PD-L1 blockade therapy. (B) In tumors without cell-intrinsic PD-L1 expression, tumors (or tumor clones) with low immunogenicity (“cold” tumors) or costimulation may not respond to anti-PD-1/PD-L1 therapy, whereas tumors (or tumor clones) with a high neoantigen load elicit antitumor T cell responses (“hot”) but their response to anti-PD-1/PD-L1 therapy varies. Antigen-specific CD8⁺ T cells secrete IFN-γ, which may turn PD-L1⁻ tumors into PD-L1⁺ tumors infiltrated with PD-L1⁺ macrophages, dendritic cells, and T cells. However, if tumors do not have IFN-γ receptors or have JAK2 mutations, tumors may remain PD-L1⁻ and not respond to anti-PD-1/PD-L1 treatment or respond if PD-L1 is induced on non-tumor immune cells. In PD-L1⁺ tumors, prolonged antigen stimulation gradually induces PD-1 expression on antigen-specific T cells. PD-1 ligation with PD-L1 induced on tumors, antigen-presenting cells, and T cells in hot tumors in turn suppresses antitumor function of effector T cells, leading to T cell “exhaustion” (a term initially used for T cell dysfunction during chronic viral infection). Early-phase T cell “exhaustion” is plastic and can be reversed by PD-1/PD-L1 blockade; in contrast, if T cell dysfunction is fixed after terminal differentiation, “deeply exhausted” T cells cannot be rescued by PD-1/L1 blockade. Inflexibility in transcriptional and epigenetic programs may contribute to the therapeutic irreversibility of deeply exhausted T cells. Potential markers suggested by studies in tumor models, viral infection models, and cancer patients are summarized below the labels for these two different dysfunctional stages of PD-1⁺CD8⁺ T cells. * indicates disparities in PD-1 levels in the literature (please refer to the text for details).