|Title:||Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy||Authors:||Lu C.-S.
|Issue Date:||2020||Publisher:||BMJ Publishing Group||Journal Volume:||8||Journal Issue:||2||Start page/Pages:||e001392||Source:||Journal for ImmunoTherapy of Cancer||Abstract:||
Background The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear. Methods Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo. Results Pemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth. Conclusions Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment. ?
|ISSN:||2051-1426||DOI:||10.1136/jitc-2020-001392||metadata.dc.subject.other:||carboplatin; CD69 antigen; cisplatin; fluorouracil; gamma interferon; immune checkpoint inhibitor; immune checkpoint protein; immunoglobulin enhancer binding protein; interleukin 2; luciferase; pembrolizumab; pemetrexed; programmed death 1 ligand 1; programmed death 1 receptor; reactive oxygen metabolite; receptor type tyrosine protein phosphatase C; thymidylate synthase; tumor necrosis factor; antineoplastic agent; pemetrexed; A-549 cell line; animal model; animal tissue; antineoplastic activity; Article; CD4+ T lymphocyte; CD8+ T lymphocyte; cell viability assay; CL1-5 cell line; coculture; controlled study; CT26 cell line; enzyme linked immunosorbent assay; flow cytometry; fluorescence activated cell sorting; human; human cell; immunoblotting; immunohistochemistry; Jurkat cell line; lymphocytic infiltration; mouse; NCI-H1299 cell line; non small cell lung cancer; nonhuman; PC-9 cell line; peripheral blood mononuclear cell; protein expression; radioimmunoprecipitation; real time reverse transcription polymerase chain reaction; RNA interference; RNA sequencing; signal transduction; spectrofluorometry; synergistic effect; T lymphocyte activation; T-47D cell line; transcription initiation; tumor microenvironment; tumor volume; tumor xenograft; animal; drug therapy; nude mouse; pharmacology; tumor cell line; tumor microenvironment; Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Immune Checkpoint Inhibitors; Mice; Mice, Nude; Pemetrexed; Signal Transduction; Tumor Microenvironment
|Appears in Collections:||醫學系|
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