Amlexanox enhances the antitumor effect of anti-PD-1 antibody

Biochem Biophys Res Commun. 2021 Jun 30;560:1-6. doi: 10.1016/j.bbrc.2021.04.126. Epub 2021 May 6.

Abstract

Cancer immunotherapy, especially treatment with monoclonal antibodies (mAbs) that block programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling, has attracted attention as a new therapeutic option for cancer. However, only a limited number of patients have responded to this treatment approach. In this study, we searched for compounds that enhance the efficacy of anti-PD-1 mAb using mixed lymphocyte reaction (MLR), which is a mixed culture system of the two key cells (dendritic and T cells) involved in tumor immunity. We found that amlexanox enhanced production of interferon (IFN)-γ, an indicator of T cell activation, by anti-PD-1 mAb. Amlexanox also induced PD-L1 expression in dendritic cells in MLR, whereas it did not stimulate interleukin-2 production by Jurkat T cells. These results suggest that amlexanox acts on dendritic cells, not T cells, in MLR. Furthermore, it enhanced the antitumor effect of the anti-PD-1 mAb in vivo in a mouse tumor-bearing model. The combination of amlexanox and anti-PD-1 mAb increased the expression of Ifng encoding IFN-γ, IFN-γ-related genes, Cd274 encoding PD-L1, and cytotoxic T cell-related genes in tumors. In conclusion, amlexanox stimulates the antitumor effect of anti-PD-1 mAb by acting on dendritic cells, which in turn activates cytotoxic T cells in tumors.

Keywords: Cancer; Cancer immunotherapy; Cytotoxic T cell; Immunity; Interferon-γ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use*
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Dendritic Cells / metabolism
  • Female
  • Humans
  • Interferon-gamma / biosynthesis
  • Jurkat Cells
  • Lymphocyte Culture Test, Mixed
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes, Cytotoxic / metabolism

Substances

  • Aminopyridines
  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • CD274 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma
  • amlexanox