Selective targeting of tumor associated macrophages in different tumor models

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).

Evidence for interaction of the NLRP3 inflammasome and Bruton’s tyrosine kinase in tumor-associated macrophages: implications for myeloid cell production of interleukin-1beta

“…populations including dendritic and epithelial cells that also express IL-1β and are potentially not affected through BTK inhibition. [36][37][38][39] However, further studies are needed to further investigate this hypothesis. Although the 4T1 model of breast cancer has substantial levels of neutrophils, this model has been utilized previously to study TAM.…”

“…Although the 4T1 model of breast cancer has substantial levels of neutrophils, this model has been utilized previously to study TAM. 36,[40][41][42] Specifically, Makela et al demonstrated that cell tracking approaches can be utilized to visualize TAM in vivo using the 4T1 model. 43 NLRP3 expression within the tumor was not altered by the BTK inhibitor.…”

“…The trend in decreased IL-1β in vivo could be explained by a broad number of additional infiltrating cell populations including dendritic and epithelial cells that also express IL-1β and are potentially not affected through BTK inhibition. [36][37][38][39] However, additional studies are needed to further investigate this hypothesis. Additionally, ibrutinib treated mice also showed a small reduction in tumor volume, but this difference was not statistically significant as we have reported previously.…”

Role of Liver-Mediated Tolerance in Nanoparticle-Based Tumor Therapy

“…Another study using HCC cells has studied M2pep binding also to TAMs, showing selectivity for M2-type macrophages. The authors also reported about M2pep binding to KCs, though binding to TAM was higher in comparison [ 96 ]. In summary, specific targeting to liver macrophage populations has been proven to be very challenging though extremely necessary to achieve different therapeutic objectives such as NP accumulation for specific drug delivery to induce or avoid immune responses or to modulate M1/M2 macrophage balance.…”

Tumor-specific macrophage targeting through recognition of retinoid X receptor beta

“…The apparent TAM specificity of UNO may depend on a modification of the peptide that only happens on the surface of TAMs. Cieslewicz M. et al used cultured macrophages differentiated into the immune-suppressive M2 phenotype to isolate a peptide that shows a preferential binding to TAMs [20,21]. However, the receptor for this peptide has not been identified, which prevents the understanding of its TAM-targeting mechanism.…”