A combination of TLR9 agonists and an anti-PD-1 antibody has been reported effective in immunocompetent mice. However, the role of innate immunity has not yet been explained.

In a recent article published by the Cancers, by using Bio X Cell’s anti-mouse PD-1 in vivo antibodies as one of the research tools, Camelliti et al evaluated the contribution of macrophages to the effect of combinatorial immunotherapeutic treatments with TLR9 stimulation and PD-1 blockade in an ovarian cancer preclinical model.

Camelliti et al found that TLR9-stimulated macrophages, through its interaction with the fragment crystallizable (Fc) domain of the anti-PD-1 antibody, acquire an immunoregulatory phenotype leading to dampening of antitumor effect of CpG-ODN, a TLR9 agonist. The stimulation of macrophage TLRs can be achieved not only by synthetic agonists but also by molecules present in the tumour microenvironment, Camelliti et al data may suggest another possible mechanism of anti-PD- antibody therapy resistance.

 

What are toll-like receptors (TLRs)?

  • Toll-like receptors (TLRs) are receptors that are
      • expressed by an immune and nonimmune cell
      • able to recognize molecules released by pathogens

  • The engagement of TLRs by their cognate ligands provokes a potent innate immune response that leads to the activation of adaptive immunity. TLR agonists have been extensively investigated in cancer research
      • Many preclinical and clinical studies have evaluated the therapeutic potential of synthetic agonists of TLR9.

Why TLR9 agonists were studied in this experiment?

It has been reported that TLR9 stimulation can induce the expression of the immune checkpoint receptor programmed death-1 (PD-1) on different immune cells.

  • PD-1 is well known to inhibit T lymphocyte effector functions upon interaction with programmed death-ligand 1 and 2 (PD-L1 and PD-L2).
      • The PD-1/PD-Ls pathway is fundamental for maintaining self-tolerance and preventing autoimmunity.
      • Tumour cells exploit this pathway to escape immune elimination.
    •  
  • Some evidence suggested that PD-1 blockade can produce desired effect in tumour-bearing immunodeficient mice

Using Bio X Cell anti-mouse PD-1 in vivo antibodies as one of the research tools to study cancer immunology

  • Camelliti et al investigated the contribution of the innate immune system to the effect of combinatorial immunotherapeutic treatments with TLR9 stimulation and PD-1 blockade.

  • Athymic nude mice xenografted with IGROV-1 human ovarian cancer cells were used in this experiment.
      • IGROV-1 human ovarian cancer cell is generally considered poorly responsive to anti-PD-1 antibody therapy.
      • TLR9-stimulated macrophages, through their interaction with the fragment crystallizable (Fc) domain of the anti-PD-1 antibody, acquire an immunoregulatory phenotype leading to dampening of the antitumour effect of TLR9 agonist, the CpG-ODN.

  • The stimulation of macrophage TLRs can be achieved not only by synthetic agonists but also by molecules present in the tumour microenvironment, Camelliti et al data may suggest another possible mechanism of anti-PD- antibody therapy resistance.

  • Further studies are needed to fully identify the Fc receptors involved in the observed effect on macrophages.

Read the full article here.

Reference:

1. Camelliti, Simone et al. “Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain.” Cancers vol. 13,16 4081. 13 Aug. 2021, doi:10.3390/cancers13164081.

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