Abstract 897: Methionine restriction alters functional polarization of macrophages in a murine model of prostate cancer
Authors: Orillion Ashley , Adelaiye-Ogala Remi , Shen Li , Ciamporcero Eric , Elbanna May , Chintala Sreenivasulu , Arisa Sreevani , Elzey Ben , Kao Chinghai , Fontana Luigi , Pili Roberto 
Published: July 2016

Background: Epidemiological studies link prostate cancer (CaP) to dietary intake. Recent research has shown that individuals consuming a Western diet, high in protein, have higher circulating IGF-1 (insulin-like growth factor 1) which feeds into the nutrient sensing mTOR pathway. This evolutionarily conserved pathway is central to the development of advanced stage and castration resistant CaP. Our previous published studies have shown that dietary protein restriction inhibits tumor growth via mTOR pathway alteration and reduces circulating IGF-1 levels in vivo. The current study hypothesizes that dietary methionine restriction will alter the functionality of immune cells enhancing the ability of the immune system to respond to cancerous insults.

Methods: Mice were fed low (7% protein) or control protein (21% protein) diets. In a prevention study mice consumed modified diets for four weeks prior to being inoculated with CaP tumors. In a simultaneous intervention study mice were inoculated with CaP tumors first then four weeks later were placed on the modified diets.

Results: In the low protein diet group, we observed that pro-tumor M2 polarized macrophages were significantly reduced in the tumor microenvironment (TME) for both prevention (p = 0.012) and intervention diet (p = 0.0003) studies as compared to the control diet, in addition to observation of mTOR inhibition and IGF-1 reduction. Besides protein content in diet, we also analyzed the amino acid composition. Multiple groups have shown that methionine restriction (MR) inhibits mTOR activation, alters the immune system, and prolongs the survival of rodents. The mechanism by which MR impacts the innate immune system is still poorly understood. In our preliminary in vitro studies, we observed that modification of a single amino acid (AA), such as methionine, is sufficient to inhibit activation of both the mTOR pathway and M2 polarization (Arginase1 qRT-PCR of two samples in quadruplicate (p = 0.0732)), while increasing the presence of M1 macrophage marker iNOS (p = 0.2689) in bone marrow derived macrophages (BMDMs). Thus, we hypothesize that modulating specific amino acids in the diet is sufficient to alter macrophage expression of M1/M2 characteristics, and their functions in the TME.

Conclusions: Preliminarily data shows that altering one specific AA intricately linked to the mTOR pathway is sufficient to change macrophage polarization status both at the protein and gene expression levels, suggesting that dietary alteration of a single AA is capable of altering macrophage function. The results of the study provide the basis for translational use of dietary means to alter the immune system and improve the therapeutic effects of immunotherapies.

Citation Format: Ashley Orillion, Remi Adelaiye-Ogala, Li Shen, Eric Ciamporcero, May Elbanna, Sreenivasulu Chintala, Sreevani Arisa, Ben Elzey, Chinghai Kao, Luigi Fontana, Roberto Pili. Methionine restriction alters functional polarization of macrophages in a murine model of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 897.