Abstract B49: Precision targeting of M2-like macrophages by the innate defense regulator RP-182 in pancreatic cancer and noncancerous diseases

Immunologically “cold” tumors are not responsive to current immunotherapies. The impact of T-cell activation with immune checkpoint inhibition or vaccines is limited in these cancers by a lack of intertumoral T cells or an “exhausted” T-cell phenotype, which are frequently induced by abundant immune-suppressive cues from intertumoral innate immune cells. Tumor-associated macrophages (TAMs) are a major cell population of the tumor microenvironment and play a key role in promoting tumor progression in many solid organ cancers. During cancer progression, tumoral and microenvironmental cues educate TAMs towards a M2-phenotype that nurtures cancer stem cells, 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 is a 10mer striapathic peptide with immunomodulatory function that 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 antitumor immunity, findings also seen in other syngeneic cancer models that include variety of murine and human (PDX) 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 lectin receptor CD206. This is associated with improved clinical outcome in transgenic mice with pancreas cancer. Similarly, RP-182 selectively reduces immune-suppressive M2-like macrophages, a finding also made in a noncancerous 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. Citation Format: Rushikesh Sable, Jesse Jaynes, Michael Ronzetti, Wendy Guzman, Zachary Knotts, Natalia de Val, Juan Morgan, Clayton Yates, Baljinnyam Bolormaa, Udo Rudloff. Precision targeting of M2-like macrophages by the innate defense regulator RP-182 in pancreatic cancer and noncancerous diseases [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B49.