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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.

Background: Prostate cancer (PCa) is higher among African American (AA) than Caucasian Americans (CA). AAs are more frequently diagnosed with PCa with worse prognoses than CAs. Support of a genetic component to the high incidence and mortality rate in AA men is based on epidemiologic studies of men with similar genetic backgrounds. For instance, men in Ghana and Nigeria also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom. Multiple reports indicate that PCa aggressiveness is the result of cancer stem cells (CSC). Furthermore, people of African Ancestry have been reported to have increased stemness gene signature in multiple tumor types. CD133, which is a well-known progenitor/stem cells marker, and is associated with prostate tumor relapse and metastasize due to the existence of prostate cancer stem cells (PCaCSC) has been well characterized, however, its role in prostate cancer racial disparity is unknown. Therefore, our objective is to analyze the significance of CD133 as a disparity stem cell biomarker in AA and CA patients with late-stage PCa. Methods: TGCA Prostate Dataset was used for patient data. The R and R studio statistical software was used for the analysis, and for the survival analysis, Log-Rank test was used to determine survival. H & E was used to determine the presence of prostate cancer and tumors were scored using Gleason grading. CD133 protein location and expression was determined by IHC, and quantified using Aperio imaging software. Results: We analyzed genomic data in TGCA for correlation between CD133 over-expression and worst patient survival outcome. Survival analysis indicated a poorer survival outcome in the AA with high CD133 expression during late-stage PCa compare to the CA with the same stage of PCa. Furthermore, the addition of CD44 furthermore increased the significant difference between the stem cell population (p= 0.04) between AA and CA patients. To confirm these results, we evaluated CD133 expression in (Gleason =7) PCa tumor from AA and CA patients and compared them to BPH. As in the TCGA data, we observed increased CD133 expression in AA patients. Conclusion: Elevated CD133 shows an association with patients with African Ancestry. Further studies are necessary on a larger series of cases to elucidate the role of CD133 in the development and progression of prostate cancer and its suitability as a prognostic biomarker. Citation Format: Benjamin Adu-Addai, Ahmad B. Salam, Ruksana Amin, Honghe Wang, Huixian Lin, Anghesom Ghebremedhin, Jason White, Jesse M. Jaynes, Clayton Yates. CD133 as a disparity stem cell biomarker in African Americans with late-stage prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-181.

Background: Tumor associated M-ϕs (TAMs) have a complex etiology as a result of soluble factors secreted by prostate tumor cells, creating an immunosuppressive micro-environment (M-E) for the progression of late stage PC that has metastasized to the bone. The result is an M2-like polarization that expresses a number of M2-TAM specific markers, including CD206. Therapeutic targeting of TAMs has proven to be a challenge, due partly to a lack of understanding of the function of this biomarker and the bi-directional effects of TAMs on tumor cells. Our objective is to characterize the CD206 receptor in PC patients, and to test the potential of a novel engineered CD206 targeted peptide (T-P) to reverse the immune-suppressive M-Env in late stage PC. Methods: The TGCA Prostate Dataset was used for patient data and R software was used for informatics analysis. Small-angle X-ray scattering (SAXS) was used to generate the NMR structure of CD206. Peptide binding to the naïve CD206 receptor was determined in silico using PIPER, and was validated by Surface Plasmon Resonance (SPR). In vivo efficacy of CD206 T-P was determined in mice inoculated with PC-3 intratibially. Mice were treated with peptide alone, daily or twice a week at 10, 20, and 50mg/Kg, as a monotherapy or in combination with 20mg/Kg Docetaxel (DTX) over a 21day period. CD86 (M1) and CD206/CD163 (M2-TAM) markers and pro-inflammatory cytokines were determined by FACS. Bone osteolysis was determined by IHC of the entire bone, and bone turnover was determined by IHC analysis of RANKL. Results: TCGA data showed that over-expression of CD206 in Human PC is significantly associated with poor survival. In silico analyses showed the T-P exhibited strong affinity towards CD206 and was validated by SPR (Kd =3.57 µM). In bone-metastatic xenograft models of CRPC (PC-3), the flux differential of relative fluorescence in IVIS imaging showed peptide alone (at 20mg/kg qD sQ) decreased fluorescence by 64.36% compared with the untreated group. FACS analyses of M1/M2 markers CD86/CD206 in mice treated with peptide showed a 33.87 fold decrease in CD206 (M2-TAM) expression and a 7.6 fold increase in CD86 (M1-TAM) expression, compared with only a 4.4 fold decrease in CD206 expression and 0.44 fold decrease in CD86 expression in DTX treated mice. Stem cell marker CD133 showed a 4.7 fold decrease expression compared to the untreated group further suggesting that TAM repolarization reversed the immunosuppressive M-E. X-ray of tumors in bone suggests a reduction of osteolysis and was confirmed by IHC staining and analysis of whole bone showing fibrous and inflammatory remodeling patterns of tumor regression in the peptide only group. Conclusion: These results suggest that the novel engineered CD206 T-P repolarizes M2-TAM phenotype to M1-TAM which reverses the immunosuppressive cancer M-E in late stage PC. Citation Format: Ahmad B. Salam, Benjamin Adu-Addai, Huixian Lin, Anghesom Ghebremedhin, Jason White, Ruksana Amin, Balasubramanyam Karanam, George Martin, Charles Garvin, Henry Lopez, Jesse M. Jaynes, Clayton Yates. Novel synthetic peptide targets CD206 receptor promoting the repolarization of prostate cancer (PCa) TAMs and increase the efficacy of conventional prostate cancer therapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4062.