Abstract 2360: Targeting IL-4R alpha on tumor-associated macrophages as a therapeutic strategy for prostate cancer

Abstract

Abstract Prostate cancer tumor growth and disease progression are highly influenced by non-cancerous host cells within the tumor microenvironment including immune cells. High prevalence of tumor-associated macrophages (TAMs) in tumor biopsies is associated with poorer outcomes. TAMs comprise as much as 50 percent of prostate cancer tumors making them an abundant and critical target for treating prostate cancer. Macrophages adopt different functions in response to signaling molecules in their environment. The majority of prostate cancer TAMs resemble alternatively-activated M2 macrophages which, in healthy individuals, are primarily involved in wound healing. M2 TAMs behave similarly to wound-healing M2s by promoting cancer progression and immune suppression. Macrophages are converted to M2s when the signaling molecules interleukin-4 (IL-4) or IL-13 bind IL-4 Receptor Type I or II. Both of these receptor complexes contain the IL-4 receptor alpha subunit and signal through STAT6 to regulate downstream gene transcription and conversion to M2. Due to the central role of IL-4R alpha in tumor-promoting M2s, we hypothesize that disrupting IL-4R alpha signaling will undermine the tumor-promoting capabilities of M2-like TAMs. Using human macrophages cultured in vitro, we detect IL-4R alpha expression in non-malignant human macrophages by qPCR and immunoblot, critical data that is absent in the current literature. Additionally, using the FDA-approved antibody dupilumab, we show that antagonizing IL-4R alpha prevents STAT6 phosphorylation both before and after macrophages have been converted to M2s. Additionally, we show that dupilumab mitigates the M2 characteristics of these macrophages by nanostring analysis of M2-associated genes and ELISA of immunosuppressive cytokines. These data provide evidence that targeting IL-4R alpha on human macrophages impairs tumor-promoting M2 functions. To assess IL-4R alpha expression on TAMs in vivo, we used the HiMyc and TRAMP transgenic mouse models. These mice develop spontaneous prostate cancer tumors and are more accurate representations of the primary tumor microenvironment than injected tumor models (i.e. subcutaneous and orthotopic models). Using nanostring analysis and immunohistochemistry of prostates from 8-week-, 6-month-, and 12-month-old mice, we assessed immune cell infiltration levels, M2 characteristics of TAMs, and IL-4R alpha expression of TAMs. This data provides evidence for the M2-like characteristics of TAMs and IL-4R alpha as a viable TAM target. Subsequent experiments will include assessing IL-4R alpha expression on TAMs in human tumors using prostate cancer tissue microarrays. Moreover, we will continue to investigate the therapeutic potential of antagonizing IL-4R alpha through in vivo studies. In conclusion, these data implicate targeting IL-4R alpha as a promising therapeutic strategy for targeting TAMs in prostate cancer. Citation Format: Amber E. De Groot, Kayla Myers, Sarah R. Amend, Kenneth J. Pienta. Targeting IL-4R alpha on tumor-associated macrophages as a therapeutic strategy for 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 2360.