Dietary Protein (Methionine) Restriction Affects the Tumor Microenvironment by Inducing Macrophage Polarization
Orillion, Ashley R.
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Adherence to American Cancer Society guidelines on diet, physical activity, and maintenance of a healthy body weight are well established methods of reducing cancer incidence and mortality. However, the impact of dietary modifications on the immune infiltrates into the tumor microenvironment has not been well studied. Here, we examined the link between dietary protein/amino acid restriction and alterations of tumor associated macrophages. Restriction of AAs methionine and cystine resulted in an increased polarization toward pro-inflammatory M1 phenotype. An in vitro functional study demonstrated that amino acid restricted M1 & M2 macrophages were functionally more similar to an M1 tumoricidal, pro-inflammatory phenotype. Moreover, mice fed a low protein or methionine/cystine restricted diet exhibited reduced tumor growth, reduced infiltration of M2, pro-tumor, macrophages, and increase in responsiveness to immunotherapy treatment (anti-PD-1 & survivin vaccine). We further identified an amino acid restriction dependent increase in ROS production and pro-inflammatory cytokine release, coupled with blunted mTOR signaling and enhanced Atf4 and Nfat5/Ccl2 activity, indicative of a mechanism by which dietary amino acid restriction inhibits M2 activity and enhances M1 activity in the tumor microenvironment. Taken together, this study provides evidence that dietary protein / amino acid restriction reduces tumor promoting macrophage activity and enhances the tumoricidal capacity of the innate immune system in the tumor microenvironment, and suggests that dietary protein restriction may play a role as a therapeutic strategy in cancer patients receiving immunotherapies.