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

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-kappa B pathway was one of the master regulators in TAMs manipulation. Inhibition of NF-kappa B pathway could achieve both repolarization 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-kappa B pathway was loaded in mannose modified lipid nanoparticles (M-IMD-LNP). Then, PD-1 antibody and M-IMD-LNP were coloaded 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-kappa B 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-kappa B 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.

Automated summary

Manipulation of tumor-associated macrophages (TAMs) has been identified as a key factor in improving immunotherapies, with inhibition of the NF-kappa B pathway potentially impacting both PD-1/PD-L1 and NF-kappa B pathways simultaneously. Co-loading PD-1 antibody and NF-kappa B pathway inhibitor in nanocarriers has shown promising results in enhancing the efficacy of immunotherapies.