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Local Administration of Caloric Restriction Mimetics to Promote the Immune Control of Lung Metastases.

ABSTRACT: Caloric restriction mimetics (CRMs), compounds that mimic the biochemical effects of nutrient deprivation, administered via systemic route promote antitumor effects through the induction of autophagy and the modulation of the immune microenvironment; however, collateral effects due to metabolic changes and the possible weight loss might potentially limit their administration at long term. Here, we investigated in mice local administration of CRMs via aerosol to reduce metastasis implantation in the lung, whose physiologic immunosuppressive status favors tumor growth. Hydroxycitrate, spermidine, and alpha-lipoic acid, CRMs that target different metabolic enzymes, administered by aerosol, strongly reduced implantation of intravenously injected B16 melanoma cells without overt signs of toxicity, such as weight loss and changes in lung structure. Cytofluorimetric analysis of lung immune infiltrates revealed a significant increase of alveolar macrophages and CD103+ dendritic cells in mice treated with CRMs that paralleled an increased recruitment and activation of both CD3 T lymphocytes and NK cells. These effects were associated with the upregulation of genes related to M1 phenotype, as IL-12 and STAT-1, and to the decrease of M2 genes, as IL-10 and STAT-6, in adherent fraction of lung immune infiltrate, as revealed by real-time PCR analysis. Thus, in this proof-of-principle study, we highlight the antitumor effect of CRM aerosol delivery as a new and noninvasive therapeutic approach to locally modulate immunosurveillance at the tumor site in the lung.

SUBMITTER: Le Noci V

PROVIDER: S-EPMC6609366 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Local Administration of Caloric Restriction Mimetics to Promote the Immune Control of Lung Metastases.

Le Noci Valentino V Sommariva Michele M Bianchi Francesca F Triulzi Tiziana T Tagliabue Elda E Balsari Andrea A Sfondrini Lucia L

Journal of immunology research 20190620

Caloric restriction mimetics (CRMs), compounds that mimic the biochemical effects of nutrient deprivation, administered via systemic route promote antitumor effects through the induction of autophagy and the modulation of the immune microenvironment; however, collateral effects due to metabolic changes and the possible weight loss might potentially limit their administration at long term. Here, we investigated in mice local administration of CRMs via aerosol to reduce metastasis implantation in ...[more]

PMID: 31321243

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Project description:Mice and diets. One-month-old male mice of the long-lived B6C3F1 strain were purchased from Harlan (Indianapolis, IN) and maintained as described after weaning (15). Mice were housed in groups of 4 per cage and fed a non-purified diet, PMI Nutrition International Product #5001 (Purina Mills, Richmond, IN). At 5 months of age, the mice were individually housed, and randomly assigned to one of two groups, control (CON) or long-term CR (LTCR). CON mice were fed 93 kcal per week of a defined control diet (AIN-93M, Diet No. F05312, BIO-SERV). LTCR mice were fed 52.2 kcal per week of a defined CR diet (AIN-93M 40% Restricted, Diet No. F05314, BIO-SERV). The LTCR mice consumed approximately 40% fewer calories than mice in the CON mice. The CR diet was enriched so that the CR mice consumed approximately the same amount of protein, vitamins, and minerals per gram body weight as the control mice. Experimental design. At 20 months of age, cohorts of mice in the CON group were randomly assigned to one of 7 experimental groups (Fig. 1). A CON group continued to be fed 93 kcal per week of control diet for 8 weeks. A CR8 group was fed 77 kcal per week of CR diet for 2 weeks, followed by 52.2 kcal per week of CR diet for 6 weeks. The remaining dietary groups were fed the control diets containing, respectively, metformin (MET; Sigma, St. Louis, MO), glipizide (GLIP; Sigma), GLIP plus MET (GM), rosiglitazone (ROS; Avandia, SmithKline Beecham) or soy isoflavone extract (SOY; NOVASOY 400, Life Extension Foundation) for 8 weeks at the dosages indicated in Table 1. The drugs were mixed with powdered control diet and cold-pressed into one gram pellets (BIO-SERV Inc.). At 0900, all mice were fed 2/7 of the weekly allotment of food on Monday and Wednesday and 3/7 on Friday. The mice had free access to acidified tap water. They were fasted for 48 hours and killed by cervical dislocation at 22 months of age. No signs of pathology were detected in the animals used for the studies reported (n=4 per group). Organs were removed rapidly, flash frozen, and stored in liquid nitrogen. The weights of the mice were monitored bi-weekly. Mouse weights are given in Table 1. Measurement of specific mRNA levels. Liver total RNA was isolated as described from livers of pathology-free mice in each group (n=4 per group) (13). mRNA levels were measured using Affymetrix mouse U74Av2 arrays according to standard Affymetrix protocols (Affymetrix). Probe set expression measurement and normalization. After hybridization and scanning, raw image files were converted to probe set data (*.CEL files) using Microarray Suite (MAS 5.0). Probe set data from all 32 arrays were simultaneously analyzed with the Robust multichip Average (RMA) method to generate normalized expression measures for each probe set (Fig. 2; Ref. 24) The data were further filtered to exclude probe data sets that were Absent across all 32 arrays according to the MAS 5.0 detection algorithm (1,47).

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Local Administration of Caloric Restriction Mimetics to Promote the Immune Control of Lung Metastases.

Publications

Local Administration of Caloric Restriction Mimetics to Promote the Immune Control of Lung Metastases.

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