Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function

Abstract

Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the addition of anti-TLR2 or anti-TLR4 blocking antibodies. In vivo, we maximized the antitumor activity of IFNα co-expressing in the liver a SR-B1 ligand and IFNα by adeno-associated viruses. This gene therapy strategy eradicated liver metastases from colon cancer with reduced toxicity. On the other hand, genetic and pharmacological inhibition of SR-B1 blocks the clathrin-dependent interferon receptor recycling pathway with a concomitant reduction in IFNα signaling and bioactivity. This effect can be applied to enhance cancer immunotherapy with oncolytic viruses. Indeed, SR-B1 antagonists facilitate replication of oncolytic viruses amplifying their tumoricidal potential. In conclusion, SR-B1 agonists behave as IFNα enhancers while SR-B1 inhibitors dampen IFNα activity. These results demonstrate that SR-B1 is a suitable pharmacology target to enhance cancer immunotherapy based on IFNα and oncolytic viruses.

Trial watch: Immune checkpoint blockers for cancer therapy

“…A conspicuous amount of literature dealing with preclinical and translational aspects of ICB-based immunotherapy has appeared in peer-reviewed journals after the publication of our latest Trial Watch on the same topic (March 2015). 3 Of this exceptionally abundant literature, we found of particular interest several works focusing on resistance mechanisms and potential strategies for circumventing them, including the work of: (1) Ghoneim and collaborators (from the St. Jude Children's Research Hospital, Memphis, TN, US), who identified an epigenetic reprogramming mechanism relying on de novo DNA methylation 78 that restricts T cell expansion and clonal diversity upon PD-1 blockade; 79 (2) Benci and colleagues (from the University of Pennsylvania, Philadelphia, PA, US), who characterized a type I and type II interferon (IFN)-driven [80][81][82] signaling pathway though which cancer cells overexpress ligands for multiple T-cell inhibitory receptors to exacerbate local immunosuppression; 83 (3) Gao and co-workers (from the University of Texas MD Anderson Cancer Center, Houston, TX, US), who demonstrated that defects in interferon gamma (IFNG) [84][85][86][87] signaling are associated with hyporesponsiveness to CTLA4 blockade in mouse tumors models 88 as well as in melanoma patients; 44 (4) De Henau et al (from the Memorial Sloan Kettering Cancer Center, New York, NY, US) and Kaneda et al…”

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

“…This antiviral effect was not observed upon expression of IFN-α alone or other potent proinflammatory cytokines such as IL-12. Virus elimination was not dependent on T, B, Natural Killer cells and was probably due to a phenomenon of intrinsic immunity mediated by intracellular antiviral proteins [77]. This complex system was exploited to design a novel anti-tumor strategy based on a system of selfinactivating AAVs.…”

“…Interestingly, the signaling pathway involving SR-B1 was not induced by traditional TLR2 or TLR4 ligands, indicating an active role of SR-B1 in the signaling pathway. The potential of this novel SR-B1 activity was highlighted when L37, an SR-B1 ligand, was combined with interferon alpha (IFN-α) [77]. Sustained expression of IFN-α and L37pA in murine livers by adeno-associated viruses (AAVs) triggered a potent anti-AAV response that partially eliminated the adeno-associated genomes.…”

“…Similarly, it has been recently shown that the apolipoprotein A-I mimetic peptide L37pA, serum amyloid A and lipid-free apolipoprotein A-I were able to trigger pro-inflammatory signaling in several mose cell lines (L929, 3T3, CT-26) and human cells (monocytes, hepatic HepaRG and fibroblast BJ cells), mediated by SR-B1 in a TLR2-and TLR4-dependent manner [77]. Native HDLs failed to induce this pathway, indicating a predominant role of lipid associated with the lipoproteins in the anti-inflammatory activity of SR-B1 [77]. The exposure of non-lipidated amphipathic molecules can be envisioned as a danger signal specifically detected by SR-B1.…”

“…There is an alternative splicing variant of SR-B1 (SR-B1.2) differing in C-terminal amino acid sequence, tissue expression pattern and ligand-binding specificity [72]. Currently, SR-B1 has been shown to also play an important role in the recognition, binding, and uptake of other endogenous and exogenous ligands, inducing an anti-inflammatory [73,74] or pro-inflammatory response [75][76][77][78] depending on the nature of the ligand, the cell/tissue type and the presence of DAMPs or MAMPs.…”