LAUSR

Innate defense regulator RP-182 targets CD206high M2-like macrophages in malignant and noncancerous diseases. Spinning ancient peptides into gold Tumors co-opt macrophages to promote tumor growth and evasion from immune surveillance. Through biophysical homology screening, Jaynes et al. identified an evolutionarily conserved motif across host defense peptides and innate defense regulators. On the basis of this motif, the authors synthesized a 10-mer peptide, RP-182, which reprograms tumor-associated macrophages and increases cancer cell phagocytosis and antitumor immune responses in murine cancer models. In models of pancreatic ductal adenocarcinoma, RP-182 improved responses to chemotherapy and checkpoint blockade. These results show that targeting subsets of tumor-associated macrophages could improve treatment for solid organ cancers and that evolutionarily conserved innate defense regulators can provide leads for potential cancer treatments. Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182–mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.