Dietary Protein Restriction Reprograms Tumor-Associated Macrophages and Enhances Immunotherapy.

Abstract

PURPOSE:

Diet and healthy weight are established means of reducing cancer incidence and mortality. However, the impact of diet modifications on the tumor microenvironment and antitumor immunity is not well defined. Immunosuppressive tumor-associated macrophages (TAMs) are associated with poor clinical outcomes and are potentially modifiable through dietary interventions. We tested the hypothesis that dietary protein restriction modifies macrophage function toward antitumor phenotypes.

EXPERIMENTAL DESIGN:

Macrophage functional status under different tissue culture conditions and in vivo was assessed by Western blot, immunofluorescence, qRT-PCR, and cytokine array analyses. Tumor growth in the context of protein or amino acid (AA) restriction and immunotherapy, namely, a survivin peptide-based vaccine or a PD-1 inhibitor, was examined in animal models of prostate (RP-B6Myc) and renal (RENCA) cell carcinoma. All tests were two-sided.

RESULTS:

Protein or AA-restricted macrophages exhibited enhanced tumoricidal, proinflammatory phenotypes, and in two syngeneic tumor models, protein or AA-restricted diets elicited reduced TAM infiltration, tumor growth, and increased response to immunotherapies. Further, we identified a distinct molecular mechanism by which AA-restriction reprograms macrophage function via a ROS/mTOR-centric cascade.

CONCLUSIONS:

Dietary protein restriction alters TAM activity and enhances the tumoricidal capacity of this critical innate immune cell type, providing the rationale for clinical testing of this supportive tool in patients receiving cancer immunotherapies.

• Authors: Ashley Orillion, Nur P Damayanti, Li Shen, Remi Adelaiye-Ogala, Hayley Affronti, May Elbanna, Sreenivasulu Chintala, Michael Ciesielski, Luigi Fontana, Chinghai Kao, Bennett D Elzey, Timothy L Ratliff, David E Nelson, Dominic Smiraglia, Scott I Abrams, Roberto Pili
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 24 Pg. 6383-6395 (12 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 30190370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Amino Acids
• Cytokines
• Dietary Proteins
• Polyamines

Topics

• Amino Acids (metabolism)
• Animals
• Cell Line, Tumor
• Cytokines (metabolism)
• Diet, Protein-Restricted
• Dietary Proteins (metabolism)
• Disease Models, Animal
• Gastrointestinal Microbiome
• Humans
• Immunomodulation
• Immunotherapy
• Macrophage Activation (immunology)
• Macrophages (drug effects, immunology, metabolism, pathology)
• Mice
• Mice, Transgenic
• Neoplasms (immunology, metabolism, pathology, therapy)
• Polyamines (metabolism)