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.

The matrix metalloproteinases (MMPs) have been implicated in a number of diseases involving inflammation or cellular invasion.' GM 6001 (FIG. 1) is an inhibitor of most of these enzymes with Ki's in the low nanomolar range. Though potent in vitro, this molecule is short-lived in circulation with a half-life of a few minutes.We show here that topical GM 6001 prevents the infiltration of inflammatory cells into the alkali-burned rabbit cornea and into phorbol ester-stimulated mouse skin. It thus prevents ulceration in the former and psoriasis-like inflammation and proliferation in the latter. When given systemically it blocks the infiltration of cells into the peritoneal cavity of mice stimulated with thioglycollate. Topical administration of this drug inhibits angiogenesis in the chick chorioallantoic membrane. When given intravenously, it inhibits angiogenesis in rat corneas implanted with a pellet containing tumor extract, a process requiring penetration of vascular basement membrane by endothelial cells. Finally, systemic GM 6001 increases survival of mice in a B16-Fl0 melanoma metastasis model, presumably by inhibiting cellular invasion or tumor growth.In addition to the potential for preventing direct destruction of connective tissue

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The effects of high-fat feeding on the development of obesity were evaluated in intercellular adhesion molecule-1 (ICAM-1) knockout and C57BL/6J (B6) male mice fed a high-fat diet for ≤50 days. Serum and tissues were collected at baseline and after 1, 11, and 50 days on the diet. After 11 days on the diet, ICAM-1-deficient, but not B6, mice developed fatty livers and showed a significant increase in inguinal fat pad weight. At day 50, ICAM-1-deficient mice weighed less, and their adiposity index and circulating leptin levels were significantly lower than those of B6 controls. To better understand the early differential response to the diet, liver gene expression was analyzed at three time points by use of Affymetrix GeneChips. In both strains, a similar pattern of gene expression was detected in response to the high-fat diet. However, sterol regulatory element-binding protein-1, apolipoprotein A4, and adipsin mRNAs were significantly induced in ICAM-1-deficient livers, suggesting that these genes and their associated pathways may be involved in the acute diet response observed in the knockout mice.

Highlights d Prior ICT is associated with longer PFS of melanoma patients treated with MAPKi d Anti-PD-1/L1 before MAPKi combination prolongs durability of tumor regression d Targeting M2-TAMs augments and CD8 + T cells abolishes priming-associated benefit d Anti-PD1/L1 plus anti-CTLA-4 priming may further control melanoma brain metastasis