PD-L1 Blockade Reinvigorates Dendritic Cells for Antitumor Immunity

PD-L1 Blockade Reinvigorates Dendritic Cells for Antitumor Immunity

Evolving Standards of Care
Jan 19, 2021
Wei Xu, MD, PhD
Xu Wei
In reference to: Mayoux M, Roller A, Pulko V, et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci Transl Med. 2020;12(534):eaav7431. 
JournalRadar.Dendritic.Xu

Checkpoint blockade with PD-1 or PD-L1 inhibitors has shown durable clinical responses across many cancer types. Previously, it had been generally believed that PD-1/PD-L1 blockade generates antitumor immunity by reinvigorating the PD-1–positive T cells; however, it had not been well understood whether PD-1 and PD-L1 inhibitors work via different mechanisms. Both antibodies inhibit PD-1/PD-L1 interaction, but fundamentally, PD-1 blockade additionally inhibits the PD-1/PD-L2 pathway, whereas PD-L1 blockade additionally inhibits the PD-L1/B7.1 pathway. More specifically, both B7.1 and PD-L1 are expressed by myeloid cells and might regulate the co-stimulatory function of CD28 on T cells. 

In their study, Mayoux et al.1 aimed to address the above questions by investigating the potential role of PD-L1 inhibitors on dendritic cells, particularly the dynamic interplay between PD-L1 and B7.1.  Although the cis interaction of PD-L1 and B7.1 had been reported previously, a conclusive quantitative measure had not been made. 

The study authors characterized various ligands on the surface of dendritic cells from patients with lung cancer and found that PD-L1 is more abundantly expressed than B7.1, therefore, setting the stage that B7.1 is more likely to be sequestered by PD-L1. Using various in vitro models, the authors provided evidence that sequestered B7.1 on dendritic cells can be released by a PD-L1 antibody to co-stimulate CD28 on T cells. Anti–PD-L1 Ab treatment renders dendritic cells with more capacity to prime T cells in vivo. This is the first piece of evidence to show that PD-L1–positive dendritic cells are direct targets of anti–PD-L1 antibodies, although they may not be the most predominant immune cell subset expressing PD-L1 in the tumor microenvironment. 

The next question is whether these findings have any clinical applications. The authors provided strong evidence that baseline dendritic cell signatures contributed to the clinical response of atezolizumab in patients with renal cell carcinoma and NSCLC. Although no direct comparison was done on how PD-1 or PD-L1 inhibitors would behave differently, this study demonstrated the mechanistic differentiation of PD-L1 inhibitors to empower dendritic cell function via the B7.1 pathway leading to enhanced T-cell immunity. The study results also implied that tumor-associated dendritic cells might be considered as a biomarker to support treatment-related decision making. It also suggests that PD-1 and PD-L1 inhibitors might synergize to promote antitumor immunity in certain conditions.


Reference:

  1. Mayoux M, Roller A, Pulko V, et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci Transl Med. 2020;12(534):eaav7431.

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About the Authors

Wei Xu, MD, PhD

Dr. Xu is vice president of New Drug Biology and Translational Medicine at Innovent Biologics, Suzhou China.