Abstract 1611: Caloric restriction potentiates the therapeutic benefit of androgen deprivation therapy and alters macrophage polarization when combined with PD1 inhibition in murine models of prostate cancer

Abstract

Abstract Background: Data from epidemiological studies have linked dietary intake to the development of prostate cancer (CaP). We have previously shown that dietary protein restriction inhibits tumor growth by modulating PI3K/mTOR signaling in vivo. Additionally we have shown that dietary methionine restriction influence macrophage polarization which enhances the ability of the immune system to fight cancer. In this study we hypothesize that caloric restriction is capable of restricting tumor growth and potentiating the antitumor effect of androgen deprivation therapy (ADT) and PD1 inhibition. Methods: We utilized two prostate cancer models for our in vivo studies; castrate resistant LuCaP 23.1 AI prostate cancer model and MYC-Driven prostate cancer model in C57BL/6 mice. Caloric restriction was carried out by exposing mice to alternating fasting either as a single intervention (in LuCaP 23.1 model) or in combination with ADT (enzalutamide or surgical castration) or PD-1 inhibition in Myc-CaP model. Tumor sizes and weights were blindly assessed during the study and upon study termination respectively. IHC staining for both Ki-67 and mTOR phosphorylation was done to assess the impact of fasting+/- ADT on tumor growth and mTOR signaling. Macrophage polarization/distribution in tumors was assessed using immunofluorescence. Blood was collected at the end of the study for future comprehensive analysis of PBMCS. Results: In both models, alternating fasting was associated with significant decrease in tumor weight at the end of study in comparison to control group (*p<0.05). In Myc-CaP model, tumor weight was significantly decreased in combined fasting and enzalutamide/castration group in comparison to the control condition (**p<0.001) but was not significantly better than either intervention alone. Similarly, fasting potentiated the therapeutic benefit of PD-1 inhibition yet it was not significant. Combined fasting and ADT was associated with significant reduction in Ki-67 nuclear expression (****p<0.0001), however it was not significantly less than either agent alone. Combined fasting and ADT was associated with significant decrease in P-mTOR expression in comparison to control mice (****p<0.0001). Although we did not observe significant change in tumor weight with combined fasting and PD-1 inhibition; fasting potentiated the influence of PD-1 on macrophage polarization. M2 macrophages were significantly less in combined treatment compared to either single intervention alone (**p<0.01). Conclusions: Caloric restriction can hinder prostate cancer growth and potentiate the therapeutic effect of ADT. Our results provide basis for the translational use of dietary modification both as preventive measure as well as a therapeutic intervention that can improve the benefit of current standard treatments. Citation Format: May Elbanna, Justin Budka, Paige Dausinas, Remi Adelaiye-Ogala, Nur Damayanti, Ashley Orillion, Eri Banno, Luigi Fontana, Roberto Pili. Caloric restriction potentiates the therapeutic benefit of androgen deprivation therapy and alters macrophage polarization when combined with PD1 inhibition in murine models of 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 1611.