Enriching the Housing Environment for Mice Enhances Their NK Cell Antitumor Immunity via Sympathetic Nerve-Dependent Regulation of NKG2D and CCR5.

Yanfang Song,Jianren Gu,Ming Yao,Qing Wang,Zihong Meng,Hong Tu,Peiying Li,Yu Gan,Yuling Shen,Yufeng Wu,Guohua Li

doi:10.1158/0008-5472.can-16-2143

Abstract

Mice housed in an enriched environment display a tumor-resistant phenotype due to eustress stimulation. However, the mechanisms underlying enriched environment-induced protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by enriched environment in murine pancreatic cancer and lung cancer models. This effect remained intact in T/B lymphocyte-deficient Rag1-/- mice, but was nearly eliminated in natural killer (NK) cell-deficient Beige mice or in antibody-mediated NK-cell-depleted mice, suggesting a predominant role of NK cells in enriched environment-induced tumor inhibition. Exposure to enriched environment enhanced NK-cell activity against tumors and promoted tumoral infiltration of NK cells. Enriched environment increased the expression levels of CCR5 and NKG2D (KLRK1) in NK cells; blocking their function effectively blunted the enriched environment-induced enhancement of tumoral infiltration and cytotoxic activity of NK cells. Moreover, blockade of β-adrenergic signaling or chemical sympathectomy abolished the effects of enriched environment on NK cells and attenuated the antitumor effect of enriched environment. Taken together, our results provide new insight into the mechanism by which eustress exerts a beneficial effect against cancer. Cancer Res; 77(7); 1611-22. ©2017 AACR.

Highlights

There is increasing interest in the influence of stressful factors on physiologic and pathologic processes
All data are presented as the mean Æ SEM
D, Cytotoxicity analysis of enriched natural killer (NK) cells from 6OHDA- or vehicle-treated tumor-bearing mice housed under enriched environment or standard environment

Summary

Introduction

There is increasing interest in the influence of stressful factors on physiologic and pathologic processes. Rearing in an enriched environment, which has been described as a rodent model of "eustress" or positive stress [1], provides more complex housing conditions with prolonged sensory, physical and social stimulation to residents compared with housing in a standard environment. In neuroscience, enriched environment exposure has been documented to elicit a number of beneficial effects [2,3,4,5,6,7,8], including reduced anxiety levels [9, 10]. Enriched environment housing facilitates improved recovery from traumatic brain injury and various neuropathologies in animal models [11,12,13]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

Methods

Results

Conclusion