<p>Ferumoxytol and CpG oligodeoxynucleotide 2395 synergistically enhance antitumor activity of macrophages against NSCLC with EGFR^L858R/T790M mutation</p>

Abstract

Purpose: Drug resistance is a major challenge for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment of lung cancer. Ferumoxytol (FMT) drives macrophage (MΦ) transformation towards a M1-like phenotype and thereby inhibits tumor growth. CpG oligodeoxynucleotide 2395 (CpG), a toll-like receptor 9 (TLR9) agonist, is an effective therapeutic agent to induce anticancer immune responses. Herein, the effect of co-administered FMT and CpG on MΦ activation for treating non-small cell lung cancer (NSCLC) was explored. Methods: The mRNA expression levels of M1-like genes in RAW 264.7 MΦ cells stimulated by FMT, CpG and FMT and CpG (FMT/CpG) were evaluated by quantitative reverse transcription PCR (qRT-PCR). Then, the effects of FMT/CpG-pretreated MΦ supernatant on apoptosis and proliferation of H1975 cells were detected by flow cytometry, and the expression of EGFR and its downstream signaling pathway in H1975 cells were explored by western blotting. Finally, a H1975 cell xenograft mouse model was used to study the anti-tumor effect of the combination of FMT and CpG in vivo. Results: FMT and CpG synergistically enhanced M1-like gene expression in MΦ, including tumor necrosis factor-α, interleukin (IL)-12, IL-1α, IL-1β, IL-6 and inducible nitric oxide synthase (iNOS). FMT/CpG-pretreated MΦ supernatant inhibited proliferation and induced apoptosis of H1975 cells, accompanied by down-regulation of cell cycle-associated proteins and up-regulation of apoptosis-related proteins. Further studies indicated that the FMT/CpG-pretreated MΦ supernatant suppressed p-EGFR and its downstream AKT/mammalian target of rapamycin signaling pathway in H1975 cells. Furthermore, FMT/CpG suppressed tumor growth in mice accompanied by a decline in the EGFR-positive tumor cell fraction and increased M1 phenotype macrophage infiltration. Conclusion: FMT acted synergistically with CpG to activate MΦ for suppressed proliferation and promoted apoptosis of NSCLC cells via EGFR signaling. Thus, combining FMT and CpG is an effective strategy for the treatment of NSCLC with EGFR L858R/T790M mutation.

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…Macrophages exposed to poly(I:C)-nanocomplexes showed significant secretion of the T-cell attracting chemokines CXCL10 and CCL5 and improved ability to directly kill cancer cells [ 127 ]. Recently, the combination of CpG oligodeoxynucleotides (CpG; TLR9 agonist) with Ferumoxytol ® (FMT; an FDA approved drug for the treatment of iron deficiency) showed a synergistic antitumoral effect, mediated by an increased infiltration of M1-like macrophages (expressing F4/80 and iNOS) in a murine model of NSCLC [ 128 ]. A new hydrogel loaded with CpG and Doxorubicin showed also antitumoral efficacy, mediated by a decrease in M2-like TAMs and MDSCs, upon intratumoral implantation in a murine melanoma model [ 129 ].…”

The Intrinsic Biological Identities of Iron Oxide Nanoparticles and Their Coatings: Unexplored Territory for Combinatorial Therapies

“…More recently, Wang et al demonstrated that ferumoxytol is primarily internalized by macrophages through scavenger receptors, i.e., SRI/II, and not mediated by complement C3b, as these rather large nanoparticles (30 nm) do not exhibit C3b deposition on their surface [ 174 ]. Taking another approach, Wang et al proved that the intracellular TLR9-agonists CpG and ferumoxytol also synergize to promote an M1-like phenotype in macrophages with anti-tumoricidal capacity [ 175 ]. While the results outlined thus far are mainly focused on the synergy between IONPs and TLR agonists, others have demonstrated that the pro-M1/anti-tumor properties of ferumoxytol are intrinsic to the NP.…”

Core Cross‐Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages

“…[1,19] In previous studies, ferumoxytol (Feraheme, Rienso), a formulation of an iron oxide nanoparticle in a matrix of covalently crosslinked carbohydrates (polyglucose sorbitol carboxymethylether), was used as iron source. [19][20][21][22][23] Despite its approval for the treatment of iron deficiency anemia in patients with chronic kidney disease, the original intention of ferumoxytol was as a contrast agent for magnetic resonance imaging designed for minimal iron release. [24][25][26][27][28][29][30] We now propose that delivery systems which allow for controlled iron release in the TME can serve as immunotherapeutic agent.…”