Flubendazole inhibits PD-1 and suppresses melanoma growth in immunocompetent mice

Yue Li, Ben Wu, Md Jakir Hossain, Lily Quagliata, Connor O’Meara, Marc R. Wilkins, Susan Corley, Levon Khachigian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Immune checkpoint inhibitor therapy has revolutionized the clinical management of a diverse range of cancer types, including advanced cutaneous melanoma. While immunotherapy targeting the PD-1/PD-L1 system has become standard of care, overall response rates remain unsatisfactory for most patients and there are no approved small molecule inhibitors of the PD-1/PD-L1 system. Flubendazole (FLU) is an anthelmintic that has been used to treat worm infections in humans and animals for decades.

Methods: Here we tested the anti-cancer activity of systemically delivered FLU with suppression of PD-1 in immunocompetent mice.

Results: In C57BL/6J mice bearing subcutaneous B16F10 melanoma, FLU reduced both tumor growth and PD-1 protein levels without affecting levels of PD-L1. FLU’s suppression of PD-1 was accompanied by increased CD3+ T cell infiltration. Western blotting with extracts from human Jurkat T cells showed that FLU inhibited PD-1 protein expression, findings confirmed by flow cytometry. To gain mechanistic insights on FLU’s ability to suppress PD-1 protein levels, we performed bulk RNA sequencing on extracts of Jurkat T cells exposed to the benzimidazole for 4 h. From a pool of 14,475 genes there were 1218 differentially-expressed genes; 687 with increased expression and 531 with decreased expression. Among the genes induced by FLU was the AP-1 family member, JUN and surprisingly, pdcd1. KEGG pathway analysis showed FLU up-regulated genes over-represented in multiple pathways (p < 0.01), the top hit being amoebiasis. FLU also affected the expression of genes in cancer-associated pathways, both through down-regulation and up-regulation. Gene set enrichment analysis revealed a large number of immunological signature gene sets correlated with FLU treatment, including gene sets associated with T cell differentiation, proliferation and function. The AP-1 inhibitor T5224 rescued PD-1 protein expression from inhibition by FLU.

Conclusion: This study is the first to show that FLU can inhibit melanoma growth with PD-1 suppression in immunocompetent mice.
Original languageEnglish
Article number467
Pages (from-to)1-14
Number of pages14
JournalJournal of Translational Medicine
Volume21
Issue number1
DOIs
Publication statusPublished - 14 Jul 2023
Externally publishedYes

Keywords

  • Flubendazole
  • Benzimidazole
  • Melanoma
  • Programmed cell death protein-1

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