Reprogramming Tumor-Associated Macrophages To Reverse EGFR^T790M Resistance by Dual-Targeting Codelivery of Gefitinib/Vorinostat

Abstract

Gefitinib is a first-line therapy in the EGFR-mutated nonsmall cell lung cancer (NSCLC). However, the development of drug resistance is almost unavoidable, thus leading to an unsustainable regimen. EGFR mutation is the major cause responsible for the molecular-targeting therapy failure in NSCLC. Although the recently approved osimertinib is effective for the EGFR-positive NSCLC, the osimertinib-resistant EGFR mutation is rapidly developed, too. In this study, we proposed a tumor-associated macrophage (TAM) reprogramming strategy for overcoming the EGFR-associated drug resistance via a dual-targeting codelivery system of gefitinib/vorinostat that acted on both TAM with overexpression of mannose receptors and the HER-2 positive NSCLC cells. The trastuzumab-modified, mannosylated liposomal system was able to repolarize the protumor M2 phenotype to the antitumor M1 and cause the elevating ROS in the cancer cells, consequently modulating the intracellular redox balance via ROS/NOX3/MsrA axis. The suppressed MsrA facilitated the EGFR degradation through 790M oxidation by ROS, thus resensitizing the EGFR-positive cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming strategies provided a potential method for rescuing the EGFR-caused resistance to tyrosine kinase inhibitor treatment.

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

“…Huang and co‐workers designed a trastumab‐modified mannosylated liposomal formulation loading vorinostat and gefitinib to target the mannose receptor overexpressed TAMs and cancer cells in tumor ( Figure ). [ 55 ] They found that the dual targeting system is able to repolarize TAMs from protumor M2 phenotype toward M1 phenotypes and cause elevated ROS level in cancer cells to resensitize EGFR T790M –positive cells to gefitinib, thereby reversing the EGFR T790M resistance of gefitinib in NSCLC. Upon this treatment, the percentage of CD80 + macrophages (M1 phenotype) in tumor was around 22–26% but that of CD206 + macrophages (M2 phenotype) was less than 5%, indicating the superiority of this dual targeting nanosystem in repolarizing TAMs toward M1 phenotypes.…”

Overview of recent advances in liposomal nanoparticle-based cancer immunotherapy

“…Adapted with permission from ref. [60]. Copyright (2018) American Chemical Society (neoantigens) of tumor cells to achieve improved clinical performance.…”

Recent Advances in Polymeric Nanomedicines for Cancer Immunotherapy

“…In spite of above‐mentioned limitations, owing to the abundance of TAMs in tumor tissue and considerable immunological impacts on TME, TAM‐targeted therapies are universally applicable regardless of the cancer type, contributing to enhanced tumoricidal functions of T cells and NK cells. Additionally, there are various reported polymeric nanomedicines to deplete TAMs or repolarize TAMs to M1‐like macrophages by delivering colony‐stimulating factor (CSF)‐1R inhibitor, macrophage inhibitor, TLR agonists, low molecular weight of HA, ligands for C‐type lectin receptors, inflammatory cytokines such as IL‐2, iron oxide nanoparticles, and a histone deacetylase inhibitor …”