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

Abstract

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. Methods: 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. Results: 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. Conclusion: 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.

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

“…Moreover, sulfisoxazole and macitentan are FDA-approved antagonists of endothelin receptor A (ETA) which regulates the expression of a series of genes associated with exosome biogenesis, such as Rab27a and Vps4B. Both of these drugs could reduce the exosomal secretion of PD-L1 and improve the response to anti-PD-1/PD-L1 therapy in cancer, such as breast, colon, and lung cancer [ 211 , 212 ].…”

Temsirolimus Enhances Anti-Cancer Immunity by Inducing Autophagy-Mediated Degradation of the Secretion of Small Extracellular Vesicle PD-L1

“…Recently, it is reported that inhibiting sEV PD-L1 secretion could improve the efficacy of anti-PD-L1 and anti-cancer immunity because tumor-derived sEV and sEV PD-L1 contribute to tumor growth and immune evasion by inhibiting T cell activity, such as NF-κB, IL-2, and IFN-γ activation [ 38 , 39 ]. Furthermore, we previously confirmed that suppression of sEV PD-L1 secretion through the inhibition of tumor-derived sEV secretion by the ETA antagonists sulfisoxazole and macitentan caused the activation of immune cells, thereby exhibiting anti-cancer effects [ 16 , 17 , 18 ]. Next, it is known that inhibition of PD-L1 expressed by cancer cells can activate the immune system in the body [ 39 ].…”

“…Moreover, it was reported that PD-L1 secreted from the tumor sEV binds to PD-1 on immune cells and induces immune evasion, resulting in a low response to ICBT [ 13 , 14 , 15 ]. Recently, we reported a new paradigm for cancer treatment by identifying mechanisms by which endothelin A (ETA) antagonists improve anti-cancer immunity in the body by inhibiting the secretion of tumor-derived sEV and sEV PD-L1 [ 16 , 17 , 18 ]. Therefore, the inhibition of sEV secretion and PD-L1 from tumor cells can enhance the response to ICBT.…”

Development of an exosome-related and immune microenvironment prognostic signature in colon adenocarcinoma

“…In addition, exosomes are associated with immune escape that can be driven by tumor associated macrophages and neutrophils ( Kim and Bae, 2016 ). Interaction between exosome-carried programmed death ligand 1 (PD-L1) and T-cells that produce programmed death 1 (PD-1), significantly reduce the response to immune checkpoint blocking drugs ( Lee et al, 2022 ). Consequently, exosomes have emerged as one of the key mechanisms regulating the immunotherapy of malignant tumors and it is crucial to investigate exosome-related prognostic signature in COAD patients.…”