Rational combination of an immune checkpoint inhibitor with CSF1R inhibitor-loaded nanoparticle enhances anticancer efficacy.

Abstract

Since the advent of immune checkpoint inhibitors, rapid strides have been made in the realm of cancer immunotherapy. Of the abundance of infiltrating immune cells in the tumor microenvironment (TME), macrophages contribute a significant portion and make up to 50% of the tumor mass. In addition to this, the relative plasticity of macrophages makes it an attractive target to modulate macrophage functions to initiate an anti-tumor response. However, many challenges hinder this strategy. Macrophage colony-stimulating factor (MCSF) secreted by cancer cells binds to the colony-stimulating factor receptor present on macrophages and negatively influences macrophage functions. MCSF, along with a cocktail of immunosuppressive cytokines present in the TME, polarizes macrophages to an immunosuppressive pro-tumorigenic M2-like phenotype. M2-like macrophages dampen tumor response and are known to be associated with increased tumor progression and metastasis. Indeed, clinical interventions aimed to reprogram macrophage response from an M2-like tumor aiding phenotype to an M1-like tumor-killing phenotype using small-molecule inhibitors of the CSF1R axis have gathered much attention in the recent past. However, poor response and systemic toxicities observed in these therapies necessitate alternative therapeutic strategies. Furthermore, another key signaling pathway that has been recently implicated in aiding the CSF1R signaling in TAMs is the PDL1 signaling axis. Hence, in this study, we designed a self-assembled lipid nanoparticle system encompassing a potent small-molecule inhibitor of the CSF1R signaling axis, while the surface of the nanoparticle was tethered with anti-PDL1 mAb. The purpose of this is twofold; the nanoparticles can deliver the cargo in a targeted manner to PDL1 expressing M2-like macrophages while simultaneously blocking the receptor. The resulting nanoparticle system termed α-PDL1-CSF-LNP showed enhanced repolarization of M2 like macrophages in vitro while also upregulating the phagocytic index. Furthermore, suboptimal dose administration of α-PDL1-CSF-LNP in an aggressive melanoma mouse model resulted in superior anti-tumor efficacy with minimal toxicities. These results were validated by ex vivo mechanistic analysis showing that TAMs have successfully been repolarized to a predominantly M1-like phenotype. This, along with increased tumor infiltration of CD8+ T cells, worked in synergy to provide an effective anti-tumor strategy.

• Authors: Anujan Ramesh, Vaishali Malik, Hayat Anu Ranjani, Harriet Smith, Ashish A Kulkarni
• Journal: Drug delivery and translational research (Drug Deliv Transl Res) Vol. 11 Issue 6 Pg. 2317-2327 (12 2021) ISSN: 2190-3948 [Electronic] United States
• PMID: 34365577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. Controlled Release Society.

Chemical References

• Csf1r protein, mouse
• Immune Checkpoint Inhibitors
• Lipid Nanoparticles
• Liposomes
• Receptors, Colony-Stimulating Factor
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Immune Checkpoint Inhibitors (pharmacology)
• Liposomes
• Melanoma
• Mice
• Nanoparticles
• Receptors, Colony-Stimulating Factor
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• Tumor Microenvironment