Abstract 162: Immunomodulatory role of CRAMP (cathelicidin-related antimicrobial peptide) in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer deaths among males in the United States. Successful treatments for patients with metastatic PCa are limited suggesting a need for alternate targets. Recently, we identified that antimicrobial peptides in human (LL-37) and mouse (CRAMP) are positively correlated with PCa progression in humans and mice, respectively. As a host defense peptide, LL-37/CRAMP functions against microbial pathogens, and in chemotaxis of leukocytes at sites of inflammation. Preliminary studies pertaining to immunomodulation of PCa cell-derived CRAMP in situ indicated that CRAMP chemoattracts myeloid-derived suppressor cells (MDSC), a heterogeneous population of myeloid precursors that induce T cell suppression, to tumor microenvironment (TME) indicating the significance of CRAMP in pro-tumorigenic immune cell functions during PCa progression. The present study further evaluated role of CRAMP as an immunomodulator during PCa growth using transplantable mouse PCa cell line, TRAMP-C1, containing varying CRAMP expression in wild-type and CRAMP loss of function mouse (Cnlp-/-) models. Results of the study indicated targeted down-regulation of CRAMP in mouse PCa cells delays tumorigenesis in syngenic immunocompetent mouse model suggesting significance of CRAMP in PCa development. Whereas implantation of PCa cells abrogated of CRAMP resulted in retention of neutrophils and macrophages in spleen at significantly elevated levels, mice bearing CRAMP-expressing tumors displayed decreased number of neutrophils and macrophages in spleen, but increased infiltration toward TME. These results suggest tumor-derived CRAMP possibly mediates infiltration of neutrophils and macrophages toward TME from spleen. Whether the infiltrated neutrophils and macrophages correlate to pro-tumorigenic N2 and M2 cells, respectively, needs to be confirmed. Since host immune cells, mainly neutrophils, produce CRAMP and recruit additional innate effectors to inflammatory sites, we further analyzed whether host immune cell-derived CRAMP exert synergistic effects in PCa growth together with tumor-derived CRAMP by using Cnlp-/- mice. Results indicated not only comparable tumor growth kinetics, but also comparable levels of MDSC and neutrophils in TME between Cnlp-/- and wild-type mice, suggesting that tumor is a key source of CRAMP that functions as a chemoattractant of MDSC and neutrophils. Taken together, present study proposes that tumor-produced CRAMP functions as a chmoattractant for infiltration of pro-tumorigenic immune cells; MDSC, neutrophils, and macrophages that facilitate tumor growth. Citation Format: Ha-Ram Cha, Anandi Sawant, Jonathan Hensel, Carnella Lee, Selvarangan Ponnazhagan. Immunomodulatory role of CRAMP (cathelicidin-related antimicrobial peptide) in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 162. doi:10.1158/1538-7445.AM2014-162