Macitentan improves antitumor immune responses by inhibiting the secretion of tumor-derived extracellular vesicle PD-L1

Extracellular vesicles (EVs) carrying tumor cell-derived programmed death-ligand 1 (PD-L1) interact with programmed death 1 (PD-1)-producing T cells, thus significantly lowering a patient's response to immune checkpoint blockade drugs. No drug that reinvigorates CD8+ T cells by suppressing EV P...

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Bibliographic Details
Published in:Theranostics 2022-01, Vol.12 (5), p.1971-1987
Main Authors: Lee, Chan-Hyeong, Bae, Ju-Hyun, Choe, Eun-Ji, Park, Ju-Mi, Park, Seong-Sik, Cho, Hee Jin, Song, Byoung-Joon, Baek, Moon-Chang
Format: Article
Language:English
Subjects:
Animals
Antibiotics
Antibodies
B7-H1 Antigen - metabolism
Binding sites
Biosynthesis
Breast cancer
CD8-Positive T-Lymphocytes
Cell culture
Cell Line, Tumor
Extracellular vesicles
Extracellular Vesicles - metabolism
FDA approval
Flow cytometry
Humans
Immunity
Lung Neoplasms - metabolism
Lymphocytes
Mice
Mice, Nude
Nanoparticles
Programmed Cell Death 1 Receptor - metabolism
Proteins
Pyrimidines
Research Paper
Sulfonamides
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - metabolism
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Summary:Extracellular vesicles (EVs) carrying tumor cell-derived programmed death-ligand 1 (PD-L1) interact with programmed death 1 (PD-1)-producing T cells, thus significantly lowering a patient's response to immune checkpoint blockade drugs. No drug that reinvigorates CD8+ T cells by suppressing EV PD-L1 has been approved for clinical usage. Here we have identified macitentan (MAC), an FDA-approved oral drug, as a robust booster of antitumor responses in CD8+ T cells by suppressing tumor cell-derived EV PD-L1. EV was analyzed by the data from nanoparticle tracking, immunoblotting analyses, and nano-flow cytometry. Antitumor immunity was evaluated by luciferase assay and immune phenotyping using flow cytometry. Clinical relevance was analyzed using the cancer genome atlas database. MAC inhibited secretion of tumor-derived EV PD-L1 by targeting the endothelin receptor A (ETA) in breast cancer cells and xenograft models. MAC enhanced CD8+ T cell-mediated tumor killing by decreasing the binding of PD-1 to the EV PD-L1 and thus synergizing the effects of the anti-PD-L1 antibody. MAC also showed an anticancer effect in triple-negative breast cancer (TNBC)-bearing immunocompetent mice but not in nude mice. The combination therapy of MAC and anti-PD-L1 antibody significantly improved antitumor efficacy by increasing CD8+ T cell number and activity with decreasing Treg number in the tumors and draining lymph nodes in TNBC, colon, and lung syngeneic tumor models. The antitumor effect of MAC was reversed by injecting exogenous EV PD-L1. Notably, ETA level was strongly associated with the innate anti-PD-1 resistance gene signature and the low response to the PD-1/PD-L1 blockade. These findings strongly demonstrate that MAC, already approved for clinical applications, can be used to improve and/or overcome the inadequate response to PD-1/PD-L1 blockade therapy.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.68864