Dietary protein restriction reprograms tumor-associated macrophages and enhances immunotherapy

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

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6383-6395
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Orillion, A., Damayanti, N. P., Shen, L., Adelaiye-Ogala, R., Affronti, H., Elbanna, M., Chintala, S., Ciesielski, M., Fontana, L., Kao, C., Elzey, B. D., Ratliff, T. L., Nelson, D. E., Smiraglia, D., Abrams, S. I., & Pili, R. (2018). Dietary protein restriction reprograms tumor-associated macrophages and enhances immunotherapy. Clinical Cancer Research, 24(24), 6383-6395. https://doi.org/10.1158/1078-0432.CCR-18-0980