CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

Abstract

Immune modulation of macrophages has emerged as an attractive approach for anti‐cancer therapy. However, there are two main challenges in successfully utilizing macrophages for immunotherapy. First, macrophage colony stimulating factor (MCSF) secreted by cancer cells binds to colony stimulating factor 1 receptor (CSF1‐R) on macrophages and in turn activates the downstream signaling pathway responsible for polarization of tumor‐associated macrophages (TAMs) to immunosuppressive M2 phenotype. Second, ligation of signal regulatory protein α (SIRPα) expressed on myeloid cells to CD47, a transmembrane protein overexpressed on cancer cells, activates the Src homology region 2 (SH2) domain ‐phosphatases SHP‐1 and SHP‐2 in macrophages. This results in activation of “eat‐me‐not” signaling pathway and inhibition of phagocytosis. Here, it is reported that self‐assembled dual‐inhibitor‐loaded nanoparticles (DNTs) target M2 macrophages and simultaneously inhibit CSF1R and SHP2 pathways. This results in efficient repolarization of M2 macrophages to an active M1 phenotype, and superior phagocytic capabilities as compared to individual drug treatments. Furthermore, suboptimal dose administration of DNTs in highly aggressive breast cancer and melanoma mouse models show enhanced anti‐tumor efficacy without any toxicity. These studies demonstrate that the concurrent inhibition of CSF1‐R and SHP2 signaling pathways for macrophage activation and phagocytosis enhancement could be an effective strategy for macrophage‐based immunotherapy.

Tumor-Associated Macrophages: Recent Insights and Therapies

“…In the meanwhile, this drug simultaneously inhibits CSF1R and SHP-2 signaling pathways. This research provides an idea for anti-tumor therapy of macrophages and DNTs has good perspective potential for individual drug treatments (83).…”

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

“…As an example, the reprogramming of TAMs towards an M1 phenotype has been achieved by the combination of SIRPα-blocking antibodies with CSF-1R inhibitors assembled into a unique supramolecular-system. Repolarization of TAMs was associated with increased phagocytosis of cancer cells and enhanced anti-tumor efficacy [142,143].…”

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

“…The sustained reprogramming of TAMs towards M1-antitumor effectors was achieved by the self-assembled combination of SIRPα-blocking antibodies with CSF-1R inhibitors. This combined therapy activates antitumor macrophages, by hindering the CD47-SIRPα ligation, while impairing recruitment of new TAMs by inhibition of CSF-1R [ 157 , 158 ]. Clinical trials using anti-CD47 mAbs or CD47-Fc fusion proteins are on-going for the treatment of hematological cancers or refractory solid tumors in combination with anti-PD-1 therapy or with anti-CD20 (Rituximab ® ) to target B cells [ 159 ].…”