Structural homology screening of antimicrobial host defense peptides identified RP-182 – a synthetic 10-mer amphipathic analog that bound the mannose receptor (CD206) on human and murine macrophages. Binding of RP-182 to CD206 on macrophages induced phagocytosis, autophagy, and apoptosis, resulting in M2 macrophage death or reprogramming of M2 macrophages toward an M1-like phenotype. In mouse models of pancreatic cancer, RP-182 prolonged survival and suppressed tumor growth (dependent on CD8+ T cells), decreased Tregs, increased intratumoral CD8+ T cells, and synergized with gemcitabine to further increase survival.
Contributed by Anna Scherer
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 CD206(high) 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.
Author Info: (1) College of Agriculture, Environment and Nutrition Sciences, Integrative Biosciences Program, Tuskegee University, Tuskegee, AL 36088, USA. Department of Biology and Center for
Author Info: (1) College of Agriculture, Environment and Nutrition Sciences, Integrative Biosciences Program, Tuskegee University, Tuskegee, AL 36088, USA. Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. (2) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (3) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (4) Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA. (5) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (6) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (7) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (8) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (9) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (10) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (11) Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA. (12) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. (13) Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA. (14) Sequencing Facility and Single Cell Analysis Facility, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA. (15) CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Biomedical Informatics and Data Science, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA. (16) CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Biomedical Informatics and Data Science, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA. (17) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. (18) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. (19) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. (20) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. (21) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (22) Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (23) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (24) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (25) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (26) James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. (27) Sequencing Facility and Single Cell Analysis Facility, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA. (28) Basic Science Program, Frederick National Laboratory for Cancer Research, SAXS Core Facility, Center for Cancer Research of the National Cancer Institute, Frederick, MD 21701, USA. (29) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (30) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (31) Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA. (32) Section of Histopathology, National Eye Institute, Bethesda, MD 20892, USA. (33) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (34) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. (35) Department of Hemato Oncology, Seoul National University Hospital, Seoul 03080, Korea. (36) CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Biomedical Informatics and Data Science, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA. (37) MuriGenics Inc., Vallejo, CA 94592, USA. (38) Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA. (39) Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA. Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 21701, USA. (40) Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA. cyates@tuskegee.edu baljinnb@mail.nih.gov maruganj@mail.nih.gov rudloffu@mail.nih.gov. (41) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. cyates@tuskegee.edu baljinnb@mail.nih.gov maruganj@mail.nih.gov rudloffu@mail.nih.gov. (42) National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. cyates@tuskegee.edu baljinnb@mail.nih.gov maruganj@mail.nih.gov rudloffu@mail.nih.gov. (43) Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. cyates@tuskegee.edu baljinnb@mail.nih.gov maruganj@mail.nih.gov rudloffu@mail.nih.gov.
