期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 12, 期 530, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aax6337
关键词
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资金
- Intramural Research Program of the NIH, NCI, Center for Cancer Research [ZIA BC 011267]
- Intramural Research Program of the NIH, National Center for Advancing Translational Sciences (NCATS) [ZIA TR000302-02]
- Pomerenk family via the Rachel Guss and Bob Pomerenk Pancreas Cancer Research Fellowship
- NIH/NCI [U54 CA118623]
- Department of Defense Grant [PC170315P1, W81XWH-18-1-0589]
- UNCF/Merck Postdoctoral Science Research Fellowship
- Prostate Cancer Foundation Young Investigator Award
- DOE Office of Science [DE-AC02-06CH11357]
- [U54-MD007585-26 NIH/NIMHD]
- NATIONAL CANCER INSTITUTE [ZICBC011331, ZIABC011267] Funding Source: NIH RePORTER
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.
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