Precision targeting of M2-like macrophages by the innate defense regulator RP-182 in malignant and non-cancerous diseases

Authors

• JM Jaynes
• WB Guzman
• M Ronzetti
• Z Knotts
• T Aiken
• M Dashnyam
• A Singh
• R Calvo
• D Li
• T Guerin
• J White
• R Amin
• R Hughley
• L Fan
• M Ferrer
• J Morgan
• C Yates
• B Bolormaa
• U Rudloff

Abstract

Tumor-associated macrophages (TAMs) are a major cell population of the tumor microenvironment and play key role in promoting tumor progression in many solid organ cancers. During cancer progression, tumoral/microenvironmental cues educate TAMs towards a M2-phenotype which nurtures, accelerates metastasis, and confers resistance to chemotherapy. Current drug development efforts targeting TAMs primarily focus an unselective systemic inhibition of macrophage recruitment to disease sites or modulation of their immuno-cytokine profile. RP-182, a 10mer striapathic peptide with immunomodulatory function which was derived from a biophysical homology screen of carbohydrate recognition domain patterns and naturally occurring host defense peptides (HDP) and innate defense regulators (IDR). We demonstrate that RP-182 specifically and effectively binds to the mannose receptor MRC1/CD206 expressed on M2-like macrophages, induces a conformational switch of the receptor, and activates in human and murine M2-like macrophages a program of phagocytosis, autophagy, and apoptosis. In genetically engineered murine models of pancreas cancer RP-182 suppressed tumor growth, extended survival, and improved anti-tumor immunity, findings also seen in other syngeneic cancer models. RP-182 enhanced the effects of chemo- and immune checkpoint therapy. In conclusion, the RP-182 peptide depletes the immune evasive M2 population of TAMs via engagement with the M2-specific receptor CD206. This is associated with improved clinical outcome in transgenic mice with pancreas cancer. Similarly, RP-182 selective reduction of M2-like macrophages, finding also made in a non-cancerous murine fibrosis model. Collectively, preclinical findings show that HDPs/IDRs derived from biophysical homology studies effectively reduce innate immune cell subpopulations with therapeutic merit in cancerous and nonmalignant diseases.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021