Format

Send to

Choose Destination
Clin Cancer Res. 2018 Dec 15;24(24):6383-6395. doi: 10.1158/1078-0432.CCR-18-0980. Epub 2018 Sep 6.

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

Author information

1
Genitourinary Malignancies Program, Simon Cancer Center, Indiana University, Indianapolis, Indiana.
2
Department of Cellular and Molecular Biology, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York.
3
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
4
Department of Cancer Pathology and Prevention, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York.
5
Charles Perkins Centre and Central Clinical School, The University of Sydney, New South Wales, Australia.
6
Department of Urology, Indiana University, Indianapolis, Indiana.
7
Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana.
8
Center for Cancer Research, Purdue University, West Lafayette, Indiana.
9
Department of Microbiology and Immunology, Indiana University, Indianapolis, Indiana.
10
Department of Immunology, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York. rpili@iu.edu Scott.Abrams@roswellpark.org.
11
Genitourinary Malignancies Program, Simon Cancer Center, Indiana University, Indianapolis, Indiana. rpili@iu.edu Scott.Abrams@roswellpark.org.

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.

Comment in

PMID:
30190370
PMCID:
PMC6455918
[Available on 2019-12-15]
DOI:
10.1158/1078-0432.CCR-18-0980
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center