Targeted Repolarization of Tumor-Associated Macrophages via Imidazoquinoline-Linked Nanobodies.

Evangelia Bolli,David Straßburger,Karen De Vlaminck,Jo A Van Ginderachter,Sana M Arnouk,Maximilian Scherger,Lutz Nuhn,Sophie Hernot,Hans Joachim Räder,Pol Besenius,Moritz Urschbach,Judith Stickdorn,Kiavash Movahedi,Ana Rita Pombo Antunes

doi:10.1002/advs.202004574

Abstract

Tumor‐associated macrophages (TAMs) promote the immune suppressive microenvironment inside tumors and are, therefore, considered as a promising target for the next generation of cancer immunotherapies. To repolarize their phenotype into a tumoricidal state, the Toll‐like receptor 7/8 agonist imidazoquinoline IMDQ is site‐specifically and quantitatively coupled to single chain antibody fragments, so‐called nanobodies, targeting the macrophage mannose receptor (MMR) on TAMs. Intravenous injection of these conjugates result in a tumor‐ and cell‐specific delivery of IMDQ into MMRhigh TAMs, causing a significant decline in tumor growth. This is accompanied by a repolarization of TAMs towards a pro‐inflammatory phenotype and an increase in anti‐tumor T cell responses. Therefore, the therapeutic benefit of such nanobody‐drug conjugates may pave the road towards effective macrophage re‐educating cancer immunotherapies.

Highlights

MMRhigh MHC-IIlow TAMs reside in hypoxic regions of the tumor or, following chemotherapy, along blood vessels and theirMacrophages are often an integral part of the tumor immune characteristics are regulated by the hypoxic microenvironment compartment, playing key roles in tumor progression, metas- and M-CSF.[8,9] Monoclonal antibodies could be one way tasis, and resistance to anti-cancer drugs, including immune of targeting these TAMs, but these moieties have checkpoint blockers.[1,2,3] As a consequence, tumor-associated relatively large molecular weights (∼150 kDa) which further macrophages (TAMs) are considered as promising targets increase upon coupling to other molecules
IMDQ-treated MHC-IIlowMMRhigh TAMs upregulated the expression of genes typically associated with pro-inflammatory TAMs (Tnf, Il6, Il1b, Ccl5, Nos2, Ptgs2, and Cxcl10), while lowering the expression of genes associated with anti-inflammatory TAMs (Mrc1, Ccl8, and Ccl6), compared to control MHC-IIlowMMRhigh TAMs (Figure 2A)
These results prove the potential of IMDQ to reprogram the anti-inflammatory MHC-IIlowMMRhigh TAM phenotype into a more pro-inflammatory state

Summary

Introduction

MMRhigh MHC-IIlow TAMs reside in hypoxic regions of the tumor or, following chemotherapy, along blood vessels and their. Macrophages are often an integral part of the tumor immune characteristics are regulated by the hypoxic microenvironment compartment, playing key roles in tumor progression, metas- and M-CSF.[8,9] Monoclonal antibodies (mAbs) could be one way tasis, and resistance to anti-cancer drugs, including immune of targeting these TAMs, but these moieties have checkpoint blockers.[1,2,3] As a consequence, tumor-associated relatively large molecular weights (∼150 kDa) which further macrophages (TAMs) are considered as promising targets increase upon coupling to other molecules. Van Ginderachter Myeloid Cell Immunology Lab VIB Center for Inflammation Research Brussels 1050, Belgium

Results

Discussion

Conclusion