Modulation of anti-tumor immunity by the brain's reward system

Tamar L. Ben-Shaanan, Maya Schiller, Hilla Azulay-Debby, Ben Korin, Nadia Boshnak, Tamar Koren, Maria Krot, Jivan Shakya, Michal A. Rahat, Fahed Hakim, Asya Rolls

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression.

Original languageEnglish
Article number2723
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 13 Jul 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

Funding

We would like to thank Z. Ronai, N. Karin, G. Wildbaum, H. Razon, and S. Avraham for helpful discussions, and Y. Shaked for helpful advice and the B16 cell line; Y. Ofran for the Lewis Lung Carcinoma cell line and A. Aronheim for sharing the GFP mice. We would like to thank S. Schwarzbaum for editing the manuscript. We are grateful to O. Shenker, A. Grau, E. Suss-Toby, Y. Sakoury, and M. Holdengreber from the Biomedical Core Facility at the Technion Faculty of Medicine for technical support. This study was supported by the FP-7-CIG grant 618654 (A.R.), the Israel Science Foundation (ISF) grants 1862/15 (A.R.), the Adelis Foundation (A.R.), AICR (F.H. and A.R.), Colleck Research fund, and the Allen and Jewel Prince Center for Neurodegenerative Processes of the Brain. A.R. is The Howard Hughes Medical Institute (HHMI)-Wellcome Trust International scholar.

FundersFunder number
Adelis Foundation
Allen and Jewel Prince Center for Neurodegenerative Processes of the Brain
Colleck Research fund
Seventh Framework Programme618654
Association for International Cancer Research
Israel Science Foundation1862/15

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