PD05-04 INCREASED NITRIC OXIDE SUPPRESSES MACROPHAGE POLARIZATION TO AUGMENT THE EFFECT OF CSFR1 INHIBITION THERAPY AGAINST CASTRATION RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I (PD05)1 Sep 2021PD05-04 INCREASED NITRIC OXIDE SUPPRESSES MACROPHAGE POLARIZATION TO AUGMENT THE EFFECT OF CSFR1 INHIBITION THERAPY AGAINST CASTRATION RESISTANT PROSTATE CANCER Fakiha Firdaus, Manish Kuchakulla, Yash Soni, Rehana Qureshi, Derek J. Van Booven, Khushi Shah, Omar Joel Rosete, Joshua M. Hare, Ranjith Ramasamy, and Himanshu Arora Fakiha FirdausFakiha Firdaus More articles by this author , Manish KuchakullaManish Kuchakulla More articles by this author , Yash SoniYash Soni More articles by this author , Rehana QureshiRehana Qureshi More articles by this author , Derek J. Van BoovenDerek J. Van Booven More articles by this author , Khushi ShahKhushi Shah More articles by this author , Omar Joel RoseteOmar Joel Rosete More articles by this author , Joshua M. HareJoshua M. Hare More articles by this author , Ranjith RamasamyRanjith Ramasamy More articles by this author , and Himanshu AroraHimanshu Arora More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001969.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is one of the most common non-skin cancers prevailing in American males. Targeting the tumor microenvironment (TME) using colony stimulating factor 1 (CSF1R) inhibition is a promising therapy for castration-resistant prostate cancer (CRPC). However, the therapeutic response to sustained CSF1R blockade therapy (CSF1Ri) is limited as a monotherapy. In our previous studies, we demonstrated that increased nitric oxide (NO) using S-nitrosoglutathione (GSNO) suppresses the prostate cancer TME by indirectly modulating macrophage differentiation and reducing CRPC tumor burden. In this study, we investigated how increased NO augments the action of CSF1Ri against CRPC TME. METHODS: GW2580, a CSF1-receptor inhibitor was tested in-vitro as well as in-vivo, singularly and in combination with S-nitrosoglutathione (GSNO), an active NO donor. In-vivo dosage of 40mg/kg/day for GW2580 and 10mg/kg/day for GSNO were used. For evaluating the effects of treatment on macrophage polarization, U937 cells were exposed to conditioned media from 22RV1 cells, treated with NO, CSF1Ri, or combination of NO-CSF1Ri. Macrophage markers were also checked in tumor grafts using immunohistochemistry. Moreover, we evaluated the percentage of T-regs (CD4+FOXP3+) and myeloid-derived suppressor cells (MDSCs) using flow cytometry. Cytokine antibody array was performed for differential expression in treatment conditions. RESULTS: We observed that NO-CSF1Ri combination decreases CRPC tumor burden compared to NO or CSF1Ri monotherapies. Importantly, we found that the NO-CSF1Ri combination decreases the population of T-regs (CD4+FOXP3+) and myeloid-derived suppressor cells (MDSCs), inhibits the transformation of monocytes into anti-inflammatory macrophages (CD206, F4/80); thus suggesting macrophage polarization to be the mechanism of action for the NO-CSF1Ri combination. Furthermore, cytokine screening suggested that NO-CSF1Ri suppresses several important TME cytokines like IL-12, oncostatin, BLC, FGF4, GCP2, IGFBP3, IP-10, and TGFB3. Interestingly, these cytokines were minimally suppressed by CSF1Ri therapy. Taken together, these results suggest that targeting macrophage polarization via increasing NO is a promising strategy to augment the anti-tumor effects of CSF1Ri alone. CONCLUSIONS: Our findings demonstrated a direct role of increased NO-based immunotherapy to augment the action of CSF1R inhibition to suppress the macrophage polarization in in-vivo models for castration resistant prostate cancer. Source of Funding: Supported by the American Urological Association Research Scholar Award and Stanley Glaser Award to HA and in part by Clinician Scientist Development Award from American Cancer Society to RR. JMH is supported by NIH grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, and 5UM1 HL113460, and the Soffer Family Foundation © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e56-e57 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fakiha Firdaus More articles by this author Manish Kuchakulla More articles by this author Yash Soni More articles by this author Rehana Qureshi More articles by this author Derek J. Van Booven More articles by this author Khushi Shah More articles by this author Omar Joel Rosete More articles by this author Joshua M. Hare More articles by this author Ranjith Ramasamy More articles by this author Himanshu Arora More articles by this author Expand All Advertisement Loading ...