Abstract
Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.
Highlights
Cancer immunotherapy represented by the blockade of immune checkpoint PD-1/PDL1 has gained substantial progress
The CD47/SIRPα and TIGIT/poliovirus receptor (PVR) signaling pathway jointly contribute to the immunosuppressive tumor microenvironment [32]
We examined the over-expression of CD47 and PVR in a broad spectrum of cancers and tumor cell lines
Summary
Cancer immunotherapy represented by the blockade of immune checkpoint PD-1/PDL1 has gained substantial progress. The anti-PD-1/PD-L1 resistance resulting from the upregulation of immune checkpoints suggests the importance and urgency of developing new targets [1]. A combinational blockade of different targets with non-redundant functions may achieve better clinical benefits. A novel immune checkpoint T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), which always co-expresses with PD-1 on NK and T cells and symbolizes a more exhausted status, plays pivotal roles in the adaptive anti-tumor immunity by ligation with its major ligand poliovirus receptor (PVR) [2,3]. PVR was initially identified as the receptor for the human poliovirus, or as an adhesion-related molecule that mediates tumor invasion. Increasing attention has been paid to PVR in cancer immunotherapy since the verification of its role
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