Elimination of classically-activated macrophages in tumor-conditioned medium by alternatively-activated macrophages.

Fidel-Nicolás Lolo,Sergio Casas-Tintó,Cristina Rius Leiva

doi:10.1242/bio.027300

Abstract

ABSTRACTCellular interactions are critical during development, tissue fitness and epithelial tumor development. The expression levels of specific genes confer to tumoral cells a survival advantage versus the normal neighboring cells. As a consequence, cells surrounding tumors are eliminated and engulfed by macrophages. We propose a novel scenario in which circulating cells facing a tumor can reproduce these cellular interactions. In vitro cultured macrophages from murine bone marrow were used to investigate this hypothesis. M1 macrophages in tumoral medium upregulated markers of a suboptimal condition, such as Sparc and TyrRS, and undergo apoptosis. However, M2 macrophages display higher Myc expression levels and proliferate at the expense of M1. Resulting M1 apoptotic debris is engulfed by M2 in a Sparc- and TyrRS-dependent manner. These findings suggest that tumor-dependent macrophage elimination could deplete immune response against tumors. This possibility could be relevant for macrophage based anti-tumoral strategies.

Highlights

Therapeutic strategies in oncology include the adoptive transfer of anti-tumoral classically-activated macrophages (CAMs, referred to as M1) (Eymard et al, 1996)
Our results show that M1 upregulated Secreted Protein, Acidic, Cysteine-Rich (SPARC) and Tyrosyl-tRNA synthetase (TyrRS), which have previously been shown as markers of compromised cellular fitness (Casas-Tintó et al, 2015; Portela et al, 2010)
To characterize whether anti-tumor macrophages are compromised under tumoral conditions, we analyzed SPARC and TyrRS expression

Summary

Introduction

Therapeutic strategies in oncology include the adoptive transfer of anti-tumoral classically-activated macrophages (CAMs, referred to as M1) (Eymard et al, 1996). Transfer of CAMs for cellular therapy has not reached the expected results so far; exogenous activated macrophages show restricted motility and become rapidly undetectable when facing the tumor microenvironment (Shiao et al, 2011; Andreesen et al, 1990; Tveita et al, 2014). CAMs used in cellular anti-tumoral therapy might be somehow eliminated, compromising the efficiency of treatment. M1 macrophages undergo apoptosis and are engulfed by M2 macrophages Based on these observations, we propose that adoptive transfer of macrophages as an anti-tumor therapy might undergo CAM elimination, and can have an impact on the effectiveness of the treatment

Methods

Results

Conclusion