Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy

• DOI: 10.1126/sciadv.aaz8521
• Publication Date: 2020-05-22T23:14:52Z
• Authors: Stephanie J. Wang; Ran Li; Thomas S. C. Ng; Gaurav Luthria; Madeleine J. Oudin; Mark Prytyskach; Rainer H. Kohler; Ralph Weissleder; Douglas A. Lauffe...; Miles A. Miller
• Keywords: MERTK; GAS6; Tumor progression

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 among stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) some patients, which correlated with poor clinical response, coamplified bidirectional tumor-TAM signaling via receptor tyrosine kinases (RTKs) including AXL, MERTK, their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored situ single-cell activities multiple downstream RTKs, revealing TAMs enhanced bypass TAM-proximal cells. As proof-of-principle strategy block this signaling, developed multi-RTK kinase inhibitor nanoformulation that accumulated delayed disease progression. Thus, can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.