Editors' ChoiceCancer

Do dendritic cells hold the key to regulating cancer antitumor immunity?

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Science Translational Medicine  08 Jul 2020:
Vol. 12, Issue 551, eabd3081
DOI: 10.1126/scitranslmed.abd3081

Abstract

PD-L1 blockage on dendritic cells, but not macrophages, may enhance antitumor or CD8+ T cell responses leading to greater tumor growth inhibition.

Immune checkpoint inhibitors such as anti–programmed death-1 (PD-1) antibody have revolutionized cancer treatment in the past decade. Anti–PD-1 works by blocking the interaction between PD-1 and its ligand PD-L1, preventing T cell exhaustion and resulting in enhanced antitumor T cell activity. However, only a small fraction of patients responds to treatment with immune checkpoint inhibitors, and their antitumor immune mechanisms are not completely understood.

PD-L1 is expressed on tumor cells and myeloid cells, and its presence and expression have been a controversial predictive biomarker for response to immune checkpoint inhibitors in different tumor types. Recently, in addition to PD-L1 testing on tumor cells, PD-L1 expression on tumor infiltrating lymphocytes has been integrated into oncology practice.

Antigen presenting cells such as dendritic cells and macrophages express PD-L1 as well as B7-1 and B7-2, ligands for CD28 and PD-L1. Oh et al. showed that disruption of cis interactions between PD-L1 and B7-1 affects antitumor immune response by restricting PD-1 and PD-L1 interactions, leading to uncontrolled tumor growth. Although PD-L1 is mostly expressed by macrophages, dendritic cells also represent a critical source of PD-L1. Deletion of PD-L1 in dendritic cells but not macrophages enhanced antitumor CD8+ T cell responses with substantial tumor growth inhibition. Interestingly, increased PD-1, LAG3, TIM3, and thymocyte selection-associated HMG box (TOX) expression were observed with loss of PD-L1 on dendritic cells, suggesting that these CD8+ T cell exhaustion markers do not necessarily result in decreased antitumor immunity.

The results of this study shed light on the mechanisms of immune checkpoint blockage beyond the reversal of T cell exhaustion and describe the role of dendritic cells in regulating the PD-1/PD-L1 pathway. These findings suggest that blocking the PD-1 pathway with immune checkpoint inhibitors early, at the time of priming and expansion of memory T cells, could be critical in promoting antitumor immunity.

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