Selective targeting of tumor associated macrophages in different tumor models

PLoS One. 2018 Feb 15;13(2):e0193015. doi: 10.1371/journal.pone.0193015. eCollection 2018.

Abstract

Tumor progression largely depends on the presence of alternatively polarized (M2) tumor-associated macrophages (TAMs), whereas the classical M1-polarized macrophages can promote anti-tumorigenic immune responses. Thus, selective inhibition of M2-TAMs is a desirable anti-cancer approach in highly resistant tumor entities such as hepatocellular carcinoma (HCC) or breast cancer. We here examined whether a peptide that selectively binds to and is internalized by in vitro-differentiated murine M2 macrophages as compared to M1 macrophages, termed M2pep, could be used to selectively target TAMs in HCC and breast carcinoma. We confirmed selectivity of M2pep for in vitro M2 polarized macrophages. Upon incubation of suspended mixed 4T1 tumor cells with M2pep, high amounts of the TAMs were found to be associated with M2pep, whereas in mixed tumor cell suspensions from two HCC mouse models, M2pep showed only low-degree binding to TAMs. M2pep also showed low-degree targeting of liver macrophages. This indicates that the TAMs in different tumor entities show different targeting of M2pep and that M2pep is a very promising approach to develop selective M2-TAM-targeting in tumor entities containing M2-TAMs with significant amounts of the so far elusive M2pep receptor(s).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Differentiation
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Genes, myc
  • Hep G2 Cells
  • Humans
  • Liver / drug effects
  • Liver / pathology
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / pathology
  • Macrophages / classification
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Protein Binding
  • Transforming Growth Factor alpha / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Peptides
  • Transforming Growth Factor alpha

Grant support

The work was supported by grants from GRK1172 (DFG, Germany) and from the University Hospital Frankfurt (estate of Maria Christine Held and Erika Hecker, Germany). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.