Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy
- Sci Adv. 2020 May 22;6(21):eaaz8521. doi: 10.1126/sciadv.aaz8521.
- 1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
- 2. Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
- 3. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- 4. Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
- 5. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- 6. Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Interpreting how multicellular interactions in the tumor affect resistance pathways to BRAF and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via Receptor Tyrosine Kinases (RTKs) including Axl, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.