The complex role of PD-L1 in antitumor immunity: a recent update

PD-1, a member of the immunoglobulin gene superfamily, was found to be involved in programmed cell death and subsequently demonstrated to be critical for the negative regulation of T cells. Its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) interact with PD-1 and negatively regulate T cell-mediated immune responses.¹ CD80 also interacts with PD-L1 as a counterreceptor. Moreover, PD-L1 can serve as a receptor to transmit signals to T cells and tumor cells to resist immune-mediated destruction.¹ Therefore, PD-L1 can act as both a ligand and a receptor for immunoregulatory functions. This commentary will focus on the roles of various cellular sources of PD-L1 in regulating antitumor immunity.

In addition to tumor cells, activated immune cells, such as T cells, B cells, and natural killer (NK) cells, often express PD-L1.¹ PD-L1 is also commonly expressed on myeloid cells, including macrophages, myeloid-derived suppressor cells, and dendritic cells (DCs), in the tumor microenvironment.¹ The expression of PD-L1 can be upregulated in both tumor cells and normal cells by many cytokines, especially interferon-γ.¹ The contribution of PD-L1-expressing cells to antitumor T cell suppression is critical for stratifying patients for their response to anti-PD-1/PD-L1 immunotherapy and for understanding PD-L1-mediated inhibitory mechanisms in detail.

Soon after the discovery of the inhibitory role of PD-1 in autoimmune disease,¹ it was found that ectopically expressed PD-L1 in tumor cells played a T cell-inhibitory role in a syngeneic tumor model.^2–4 Subsequently, PD-L1 on tumor cells has been widely used as a biomarker or companion diagnostic for checkpoint blockade therapy. However, almost half of patients positive for tumor PD-L1 expression fail to respond, while some patients with PD-L1-negative tumors still respond to PD-L1 blockade, suggesting that the working model of how PD-1/PD-L1 signaling affects immune responses might be more complicated.⁵ Therefore, in recent years, numerous studies have focused on exploring the important roles of PD-L1 from different cell sources. Kleinovink et al., Munn et al., and Tang et al. showed that PD-L1 expression on host cells is essential for PD-L1-mediated T cell suppression.^6–8 However, Juneja et al. revealed that PD-L1 on tumor cells is sufficient for immune evasion.⁹ Noguchi et al. and Lau et al. concluded that both tumor cell PD-L1 and host cell PD-L1 are required to mediate the suppression of antitumor immunity.^10,11

To dissect the role of PD-L1 derived from different cell types in inhibiting the antitumor T cell response, PD-L1^−/− mice and PD-L1^−/− tumor cells are commonly used to exclude the contribution of PD-L1 from nontumor cells or tumor cells, respectively. Genetic disruption of PD-L1 in mice may cause more activated CD4⁺ and CD8⁺ T cell phenotypes in the tumor microenvironment. Similarly, in these models, tumor cell lines are deficient in PD-L1 during the entire tumor development period, which may lead to a different tumor microenvironment. To overcome these limitations, we established tumor models using mPD-L1-expressing tumors in hPD-L1 KI mice or hPD-L1-expressing tumors in WT mice. In our models, the immunosuppressive roles of PD-L1 in both tumor cells and nontumor cells existed during the entire tumor development and immunotherapy periods, which better resembled the natural setting. We also took advantage of anti-mPD-L1 and anti-hPD-L1 antibodies with no cross-reactivity to selectively block tumor- or nontumor-derived PD-L1. Our data indicated that blocking PD-L1 on nontumor or tumor cells could effectively reactivate tumor-specific CD8⁺ T cell responses and inhibit tumor growth in the tumor microenvironment. In addition, both tumor-derived PD-L1 and nontumor-derived PD-L1 contributed to T cell inhibition in a nonredundant manner, and blocking both sources of PD-L1 achieved synergy and resulted in the maximum antitumor effect. In addition, the expression ratio of PD-L1^tumor/PD-L1^nontumor determined their relative contributions to immune suppression.¹²

Since the expression of PD-L1 on nontumor cells is as important as that on tumor cells, there is increasing research investigating nontumor cellular sources of PD-L1, such as macrophages, NK cells, and DCs. Peng et al. and Oh et al. found that DCs represent a critical source of PD-L1 for inhibiting antitumor immunity by using mouse models with specific ablation of PD-L1 in DCs. Although macrophages are the major source of PD-L1 in tumors, DC-derived PD-L1 is critical for the regulation of the antitumor T cell response. Ablation of PD-L1 in DCs but not in macrophages enhances antitumor T cell responses and inhibits tumor growth. In addition to its typical role in regulating T cell function, PD-L1 has recently been reported to regulate the functions of DCs and NK cells.^13,14 Mayoux et al. demonstrated that DCs are a critical target of PD-L1 blockade treatment. Blocking PD-L1 on DCs dissociates B7.1/PD-L1 in cis interactions to enhance CD28 costimulation of T cells and induce T cell priming and proliferation.¹⁵ Dong et al. showed that NK cells upregulate PD-L1 expression via the PI3K/AKT/NF-κB pathway. PD-L1⁺ NK cells showed remarkably enhanced antitumor activity compared to PD-L1⁻ NK cells. PD-L1 blockade could further enhance PD-L1⁺ NK cell function through the p38 signaling pathway. This provides a potential mechanism for the antitumor efficacy of anti-PD-L1 therapy in PD-L1⁻ tumors.¹⁶

Overall, these findings shed new light on both the clinical prediction of responders and the understanding of the underlying mechanisms of PD-1/PD-L1 blockade-mediated antitumor immunity (Fig. 1).

Fig. 1. Timeline of some key discoveries and advances related to PD-L1 in antitumor immunity.

Blue boxes represent critical studies or advances related to PD-L1. PD-L1 programmed cell death 1 ligand 1, FDA the Food and Drug Administration, NK cells natural killer cells

Competing interests

The authors declare no competing interests.