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Rhinovirus Suppresses TGF-β-GARP Presentation by Peripheral NK Cells

ABSTRACT: Asthma is a chronic airway disease whose exacerbations are often triggered by rhinovirus infection. TGF-β1 induces rhinovirus replication in infected cells. Moreover, TGF-β1 is a pleiotropic mediator that is produced by many immune cells in the latent, inactive form bound to the latency-associated peptide (LAP) and to the transmembrane protein glycoprotein A repetitions predominant (GARP). In this study we wanted to investigate the effect of rhinovirus infection on the TGF-β secretion and the downstream signaling via TGF-βRI/RII in peripheral blood mononuclear cells from control and asthmatic patients after rhinovirus infection ex vivo. Here, we found a significant upregulation of TGF-βRII in untouched PBMCs of asthmatics as well as a suppression of TGF-β release in the rhinovirus-infected PBMC condition. Moreover, consistent with an effect of TGF-β on Tregs, PBMCs infected with RV induced Tregs, and TGF-βRII directly correlated with RV1b mRNA. Finally, we found via flow cytometry that NK cells expressed less GARP surface-bound TGF-β, while cytokine-producing NKbright cells were induced. In summary, we show that rhinovirus infection inhibits TGF-β release in PBMCs, which results in the activation of both Treg and NK cells.

SUBMITTER: Krammer S

PROVIDER: S-EPMC9818541 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn the tumor microenvironment (TME), the transforming growth factor-β (TGF-β) and programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling axes are complementary, nonredundant immunosuppressive signaling pathways. Studies have revealed that active TGF-β is mainly released from the glycoprotein A repetitions predominant (GARP)-TGF-β complex on the surface of activated regulatory T cells (Tregs), B cells, natural killer (NK) cells, and tumor cells. The currently available antibodies or fusion proteins that target TGF-β are limited in their abilities to simultaneously block TGF-β release and neutralize active TGF-β in the TME, thus limiting their antitumor effects.MethodsWe designed and constructed a bispecific, trifunctional antibody, namely, BPB-101, that specifically targets the GARP-TGF-β complex and/or small latent complex (SLC), active TGF-β, and PD-L1. The binding ability of BPB-101 to the different antigens was determined by ELISA, FACS, and biolayer interferometry (BLI). The blocking ability of BPB-101 to the TGF-β and PD-1/PD-L1 signaling axes was determined by reporter gene assay (RGA). The antitumor effect and biosafety of BPB-101 were determined in a transgenic mouse tumor model and cynomolgus monkeys, respectively. Stability assessments, including stability in serum, after exposure to light, after repeated freeze-thaw cycles, and after high-temperature stress tests had been completed to evaluate the stability of BPB-101.ResultsBPB-101 bound efficiently to different antigenic proteins: the GARP-TGF-β complex and/or SLC, active TGF-β, and PD-L1. Data showed that BPB-101 not only effectively inhibited the release of TGF-β from human Tregs, but also blocked both the TGF-β and PD-1/PD-L1 signaling pathways. In an MC38-hPD-L1 tumor-bearing C57BL/6-hGARP mouse model, BPB-101 at a dose of 5 mg/kg significantly inhibited tumor growth, with a complete elimination rate of 50%. Stability assessments confirmed the robustness of BPB-101. Furthermore, BPB-101 showed a favorable safety profile in nonhuman primate (NHP) toxicity studies.ConclusionBPB-101 is a potentially promising therapeutic candidate that may address unmet clinical needs in cancer immunotherapy, thus, BPB-101 warrants further clinical investigation.

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Rhinovirus Suppresses TGF-β-GARP Presentation by Peripheral NK Cells

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