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

• Published in: Nature communications 2018-07, Vol.9 (1), p.2723-10, Article 2723
• Main Authors: Ben-Shaanan, Tamar L, Schiller, Maya, Azulay-Debby, Hilla, Korin, Ben, Boshnak, Nadia, Koren, Tamar, Krot, Maria, Shakya, Jivan, Rahat, Michal A., Hakim, Fahed, Rolls, Asya
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 38/77; 631/378/371; 631/67/580; 64/60; Activation; Adrenergic Neurons - drug effects; Adrenergic Neurons - immunology; Adrenergic Neurons - pathology; Animals; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Brain; Brain tumors; Cancer; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - pathology; Circuits; Clozapine - analogs & derivatives; Clozapine - pharmacology; Dopamine - metabolism; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - immunology; Dopaminergic Neurons - pathology; Humanities and Social Sciences; Immune response; Immune system; Immunity; Immunity, Innate - drug effects; Immunologic Factors - pharmacology; Immunology; Immunosuppression; Injections, Intraventricular; Lung carcinoma; Male; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - pathology; Norepinephrine; Norepinephrine - metabolism; Reinforcement; Reward; Science; Science (multidisciplinary); Stereotaxic Techniques; Suppressor cells; Sympathetic nervous system; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - immunology; Sympathetic Nervous System - pathology; Tumor Burden - drug effects; Tumors; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - immunology; Ventral Tegmental Area - pathology; Weight reduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05283-5

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. Neural activation can have wide ranging effects beyond central and peripheral nervous system. This work shows that chemogenetic activation of the brain’s reward system ventral tegmental area (VTA) can boost mice’s immune function, confer anti-tumor immunity, and reduce tumor mass in experimental rodent models of lung carcinoma and melanoma.