Mononuclear but Not Polymorphonuclear Phagocyte Depletion Increases Circulation Times and Improves Mammary Tumor-Homing Efficiency of Donor Bone Marrow-Derived Monocytes

Abstract

Tumor associated macrophages are an essential part of the tumor microenvironment. Consequently, bone marrow-derived monocytes (BMDMs) are continuously recruited to tumors and are therefore seen as ideal delivery vehicles with tumor-targeting properties. By using immune cell depleting agents and macroscopic in vivo fluorescence imaging, we demonstrated that removal of endogenous monocytes and macrophages (but not neutrophils) leads to an increased tumor accumulation of exogenously administered BMDMs. By means of intravital microscopy (IVM), we confirmed our macroscopic findings on a cellular level and visualized in real time the migration of the donor BMDMs in the tumors of living animals. Moreover, IVM also revealed that clodronate-mediated depletion drastically increases the circulation time of the exogenously administered BMDMs. In summary, these new insights illustrate that impairment of the mononuclear phagocyte system increases the circulation time and tumor accumulation of donor BMDMs.

Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics

“…Finally, FLI and BLI are not mutually exclusive and can be used in parallel [129] , as fusion proteins [130] , and as BRET partners (section 5.2.2).…”

Immune cells as tumor drug delivery vehicles

“…Removing the spleen before injection of immune cells resulted in increased liver accumulation of these cells, but their short-term trafficking to tumors remained unaffected [328]. This key observation could indicate that the luminal surface of the tumor vasculature is saturated with endogenous immune cells, hindering injected cells to find an available attachment site [329]. Consequently, intratumoral cell accumulation is a gradual process that requires multiple days or even weeks to complete.…”

“…Interestingly, masking phosphatidylserine exposure via annexin V prevented subsequent phagocytosis and could therefore be explored as a way to decrease the arrest of adoptively transferred immune cells in organs participating in efferocytosis [333]. Our group has recently demonstrated that depleting the MPS via pretreatment with clodronate liposomes drastically increased both the circulatory half-life and tissue accumulation efficiency of infused bone marrow-derived monocytes [329]. In addition, no change in monocyte distribution pattern was observed after depletion of endogenous neutrophils [329].…”

“…Our group has recently demonstrated that depleting the MPS via pretreatment with clodronate liposomes drastically increased both the circulatory half-life and tissue accumulation efficiency of infused bone marrow-derived monocytes [329]. In addition, no change in monocyte distribution pattern was observed after depletion of endogenous neutrophils [329]. Alternative strategies could consist of depleting cells that express apoptotic markers before their infusion, or to incorporate cell surface "don't eat me" signals such as CD47 into the cellular vehicles [334].…”

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system

“…This technology rendered multiple therapeutic benefits, including an increased delivery of IL-15, an intratumoral increase of CD8 + T cells, and consequently, an improved CAR-T cell response [50] . As immune cell isolation, ex vivo manipulation and subsequent systemic re-infusion may lead to the rapid recognition of the injected cells by the mononuclear phagocyte system via e.g., efferocytosis [51,52] , we speculate that such ex vivo approaches can be refined and improved by performing direct in vivo targeting of immune cells. In vivo immune cell targeting also provides the possibility of inhibiting (or even killing) immune cells in the circulation, thereby modulating the number and type of immune cells infiltrating tumors and metastases.…”