In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4062-4062
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-4062
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink
