PD-L1/PD-1 blocking antibodies have demonstrated therapeutic efficacy across a range of human cancers. Extending this benefit to a greater number of patients, however, will require a better understanding of how these therapies instigate anticancer immunity. Although the PD-L1/PD-1 axis is typically associated with T cell function, we demonstrate here that dendritic cells (DCs) are an important target of PD-L1 blocking antibody. PD-L1 binds two receptors, PD-1 and B7.1 (CD80). PD-L1 is expressed much more abundantly than B7.1 on peripheral and tumor-associated DCs in patients with cancer. Blocking PD-L1 on DCs relieves B7.1 sequestration in cis by PD-L1, which allows the B7.1/CD28 interaction to enhance T cell priming. In line with this, in patients with renal cell carcinoma or non–small cell lung cancer treated with atezolizumab (PD-L1 blockade), a DC gene signature is strongly associated with improved overall survival. These data suggest that PD-L1 blockade reinvigorates DC function to generate potent anticancer T cell immunity.
Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of murine group 1 ILCs. Whereas cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s, persist until adulthood, and undergo a specific developmental program. Whereas embryonically derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes the full spectrum of ILC1s. Our findings uncover key ontogenic features of murine group 1 ILCs and their association with cellular identities and functions.
Recent advances in cancer immunotherapies with PD-1/PD-L1 pathway blockade have transformed the way that cancer is being treated, leading to durable responses and prolonged overall survival. The general thinking is that PD-1/PD-L1 blockade reinvigorates tumor-infiltrating PD-1+ T cells with exhausted phenotypes. However, a mechanistic understanding on why only a subset of patients (10-30%) responds to checkpoint inhibition remains largely unknown, as does the exact immune mechanism of PD-1/PD-L1 blockade. Here, we discovered that PD-L1 blockade mediates anti-tumor immunity via dendritic cells. In human blood, in vitro and ex vivo dendritic cells (DCs) express both PD-1 and PD-L1, and an activation signal via TLR agonists triggers downregulation of PD-1 to empower the T cell stimulatory capability of DCs. In contrast, tolerogenic DCs remain PD-1 positive, correlating to T cell-unresponsiveness. Anti-PD-L1 Ab directly induces maturation of DCs and renders them capable of stimulating T cell proliferation. Similarly, anti-PD-L1 Ab treatment in tumor-bearing mice induces massive infiltration and activation of CD11c+ DCs in the spleen and draining lymph node, indicating that PD-1 is a negative regulator in DCs. Furthermore, ablation of DCs prior to anti-PD-L1 Ab treatment in an established MC38 tumor model in CD11c-DTR mice suggests a crucial role of DCs in mediating response to PD-L1 treatment. In support of the preclinical evidence that DCs are the primary target of anti-PD-L1 Ab, we analyzed RNA-seq data from tumor biopsies at baseline in patients with renal cell carcinoma prior to treatment with atezolizumab and found that the abundance of genes related to cross-presenting DC subsets (such as XCR1) correlates with a survival advantage in response to atezolizumab (HR=0.13, median OS is 16.2 months in patients with DC gene score <50% versus NR (not reached) in those >50%). In conclusion, we discovered abundance of tumor-infiltrating DCs as a novel biomarker that can predict the clinical response of PD-L1 blockade. We postulate that checkpoint inhibition directly on tumor-infiltrating DCs likely contributes to amplification of Ag-specific priming of tumor-specific T cells. Citation Format: Maud Mayoux, Marieke F. Fransen, Andreas Roller, Ines Matos, Vesna Pulko, Vaios Karanikas, Pablo Umana, Christian Klein, Ferry A. Ossendorp, Wei Xu. Dendritic cells dictate the responsiveness of PD-L1 blockade in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2017-3658
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.