The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor

Abstract

Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

Distinct Capabilities in NAD Metabolism Mediate Resistance to NAMPT Inhibition in Glioblastoma

“…Others have also optimized the delivery of NAMPT inhibitors directly into the brain with nanoparticle encapsulation [ 54 ]. Finally, there is increased interest in the role of NAMPT and NAD availability in the tumour microenvironment, and recent evidence suggests that it may enhance immune checkpoint inhibitor therapy [ 55 , 56 ]. These recent discoveries reinforce the importance of NAD metabolism in GBM therapy.…”