- Poster presentation
- Open Access
Modulation of anti-tumor lymphocyte function by neurotransmitter glutamate
Journal for ImmunoTherapy of Cancervolume 2, Article number: P38 (2014)
Most research to date pertaining to neural influence on immune response involves immunosuppression via the anti-inflammatory pathway. However, there is emerging evidence indicating that neurotransmitters have the ability to promote immune activation. We are investigating whether neurotransmitters can modulate and/or activate T cell function in situations where immunosuppression is prevalent such as in the tumor microenvironment. Published work suggests that glutamate, serotonin, dopamine, and Substance P trigger immune responses such as cytokine secretion, integrin expression, and chemotaxis. We saw that both CD4 and CD8 T cells express high surface protein levels of glutamate receptor AMPA iGluR3, which is able to import Ca2+ and Na+. We also found that mGluR1 is significantly upregulated on lymphocytes upon activation. Our data further show that T cells in the tumor-draining LN and tumor-infiltrating lymphocytes have upregulated expression of iGluR3 and mGluR1. Treatment with glutamate or its receptor agonist augmented T cell proliferation following CD3-CD28-mediated TCR stimulation. Thus, modulation of glutamate receptor signaling can be useful for enhancing anti-tumor T cell immunity such as inhibition of AICD, enhancement of proliferation, and increased cytokine production [1, 2]. Indeed, overactivation of lymphocytes in multiple sclerosis is closely tied to the overexpression of AMPA GluR3 on T cells . Experiments are under way to dissect in an adoptive transfer set up whether glutamate-modulated immune effector function involves specific activation of anti-tumor lymphocytes to elicit cytolytic response that is needed to cause tumor cell death. Our findings will help identify novel neuro-immune modulators that may serve to enhance anti-tumor T cell response.
Chiocchetti A, Miglio G, Mesturini R, Varsaldi F, Mocellin M, Orilieri E, Dianzani C, Fantozzi R, Dianzani U, Lombardi G: Group I mGlu receptor stimulation inhibits activation-induced cell death of human T lymphocytes. British journal of pharmacology. 2006, 148: 760-768.
Pacheco R, Oliva H, Martinez-Navio JM, Climent N, Ciruela F, Gatell JM, Gallart T, Mallol J, Lluis C, Franco R: Glutamate released by dendritic cells as a novel modulator of T cell activation. J Immunol. 2006, 177: 6695-6704. 10.4049/jimmunol.177.10.6695.
Sarchielli P, Di Filippo M, Candeliere A, Chiasserini D, Mattioni A, Tenaglia S, Bonucci M, Calabresi P: Expression of ionotropic glutamate receptor GLUR3 and effects of glutamate on MBP- and MOG-specific lymphocyte activation and chemotactic migration in multiple sclerosis patients. Journal of neuroimmunology. 2007, 188: 146-158. 10.1016/j.jneuroim.2007.05.021.