Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy

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.

Update in TIGIT Immune-Checkpoint Role in Cancer

“…Azelnidipine is a long-acting third-generation dihydropyridine calcium channel blocker that has been approved for the treatment of hypertension. However, using the molecular operating environment (MOE) by blocking and MST binding assays, molecular docking and structural analysis of CD172a and CD112 have indicated azelnidipine’s potential relevance in cancer immunotherapy ( 171 ). Azelnidipine inhibits the innate checkpoint CD47/CD172a and the adaptive checkpoint TIGIT–CD112 pathways and has anti-cancer effects by increasing the infiltration and function of CD8 + T cell and macrophage tumor cell phagocytosis in vivo and in vitro .…”

“…Zhou et al. demonstrated that azelnidipine blocks CD47–CD172a signaling, reactivates macrophage phagocytosis, and improves antitumor immunity even in combination with radiotherapy, as shown in the MC38 murine colon adenocarcinoma cell line ( 171 ). A cancer immunotherapy antibody targeting both CD47 and TIGIT has been patented (WO2020259535).…”

The Intriguing Thyroid Hormones–Lung Cancer Association as Exemplification of the Thyroid Hormones–Cancer Association: Three Decades of Evolving Research

“…In the same context, LT3 is of great interest for four additional reasons. First, very recently, Zhou et al suggested that LT3 could be repositioned for cancer immunotherapy based on its ability to block the T Cell Immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) interaction—an emerging immune checkpoint system [ 135 ]. Second, the ability of LT3 to induce phenotypic and functional activation of DCs [ 23 ] could potentiate the promising dendritic cell-based immunotherapy in lung cancer [ 136 ].…”

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

“…13 , 97 ), an anti-hypertensive drug approved by the FDA, can be repositioned for cancer immunotherapy by dual blocking CD47/SIRP α and TIGIT/PVR pathways by co-targeting SIRP α and PVR. In vivo , azelnidipine alone or combined with irradiation can significantly inhibits the growth of MC38 tumors and CT26 tumors by enhancing the infiltration and function of CD8 + T cell in tumor 114 . As mentioned above, an increasing number of drugs have been repurposed for cancer immunotherapy, indicating a promising potential on cancer therapy.…”