Manipulation of TAMs functions to facilitate the immune therapy effects of immune checkpoint antibodies

J Control Release. 2021 Aug 10:336:621-634. doi: 10.1016/j.jconrel.2021.07.009. Epub 2021 Jul 9.

Abstract

Immune checkpoint antibodies have emerged as novel therapeutics, while many patients are refractory. Researchers had identified tumor-associated macrophages (TAMs) is the pivotal factor involved in immune resistance and that manipulation of TAMs functions would improve the immunotherapies effectively. NF-κB pathway was one of the master regulators in TAMs manipulation. Inhibition of NF-κB pathway could achieve both re-polarization M2 TAMs and downregulation the expression of programmed cell death protein 1 (PD-1) ligand 1 (PD-L1) on TAMs to improve the effect of immunotherapies. Here, IMD-0354, inhibitor of NF-κB pathway was loaded in mannose modified lipid nanoparticles (M-IMD-LNP). Then, PD-1 antibody and M-IMD-LNP were co-loaded in matrix metalloproteinase 2 (MMP2) responsive and tumor target nanogels (P/ML-NNG). P/ML-NNG could co-deliver drugs to tumor site, disintegrated by MMP2 and release drugs to different targets. Evaluation of PD-1 expression, inhibition of NF-κB pathway, expression of PD-L1 on M2 TAMs and M2 TAMs re-polarization demonstrated that P/ML-NNG could block the PD-1/PD-L1 and NF-κB pathways simultaneously. Evaluation of CD4 + T cells, CD8 + T cells, Tregs, cytokines and antitumor immunity confirmed that IMD-0354 could improve the immunotherapies effectively. Those results provided forceful references for tumor immunetherapy.

Keywords: Checkpoint blockade immune therapy; M2 TAMs re-polarization; MMP2 responsive; NF-κB pathway; Nanogels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Immunotherapy
  • Matrix Metalloproteinase 2*
  • NF-kappa B
  • Tumor Microenvironment
  • Tumor-Associated Macrophages*

Substances

  • NF-kappa B
  • MMP2 protein, human
  • Matrix Metalloproteinase 2