Observations on neuroimmunomodulation as a novel therapeutic strategy in metastasis

Dear Editors,

The essential roles of neuroimmune pathways in breast cancer metastasis have recently been described. In an excellent article, Prof. Dr. Erin has built upon previous work to demonstrate pharmacological modulation of TRPV1 expressing sensory nerve fibres and the vagus nerve may influence an anti-tumoral immune response [1]. Perineural treatment with capsaicin was used to selectively inactivate vagal nerves and was shown to increase lung metastasis from breast cancer in a murine model. As such, increased metastases were found to be due to the loss of host defenses against cancer, to which peripheral nerves including TRPV1 expressing fibres and the vagus nerve contribute. Peripheral nerve endings regulate local blood flow (and, therefore, the activity of immune cells) through vasoactive neuropeptides, and Substance P-treatment was shown to mimic the protective effect of sensory nerve fibres in diminishing metastases [1]. This is an extremely important report which highlights a potentially novel approach in cancer immunotherapy. Furthermore, this corroborates previous work suggesting a novel anti-cancer role for the vagus nerve, which may be attributable to parasympathetic and cholinergic anti-inflammatory pathways [2].

Previously, vagotomy and/or impaired vagal tone have been associated with poorer outcomes in patients with cancer. Indeed, heart rate variability, which directly correlates with the vagal tone, is an independent predictor of improved survival in patients with cancer [2]. Similarly, pharmacological activation of the vagus nerve using semapimod, galantamine, nicotine and acetylcholine have all been shown to decrease tumor growth and metastasis in experimental models [2]. To add to this, I wonder if a case can be made for electrical modulation of the vagus nerve—to possibly introduce the concept of neuroimmunomodulation in attenuating metastasis.

Firstly, vagus activation may induce systemic epigenetic anti-tumoral influences. Widespread neural and systemic epigenetic changes as a result of electrical vagal nerve stimulation (VNS) have recently been demonstrated [3]. VNS-mediated alterations in DNA methylation and histone modification were shown in stress-response signaling, in multiple inflammatory cascades and other homeostatic pathways, all of which are known to have important roles in cancer. These epigenetic changes have been put forth as a parallel effector of the established anti-inflammatory effect associated with VNS through activation of the cholinergic anti-inflammatory pathway, and these effects would be potentially harnessed surgically. Additionally, VNS modulates and influences sympathetic activity, which otherwise contributes to cancer progression. VNS is an established therapy for epilepsy, depression and other neuropsychiatric conditions and approximately 150,000 people have undergone surgical implantation of VNS [4]. Furthermore, transcutaneous VNS is being developed, which further increases the scope of delivering this therapy non-invasively.

In addition to the reduction of breast metastasis to lung and heart, VNS may offer particular advantages in attenuating brain metastasis, which is the major cause of death in breast cancer. VNS has a demonstrated anti-glutamate effect which is thought to underpin its anti-seizure effect. Recent studies have shown that paracrine glutamate signaling identical to neurotransmission strongly promotes tumorigenesis in the brain, including metastasis of breast tumors to the brain [5]. Owing to the strong similarity of such glutamatergic signaling to epileptiform glutamatergic neurotransmission (which is diminished by VNS), VNS may be especially efficacious in preventing metastasis to the brain. Furthermore, VNS-mediated epigenetic changes particularly altered neural growth and plasticity cascades [3], which are implicated in brain tumors, and VNS neuromodulation may be synergistically therapeutic.

Further mechanistic studies are indicated. As a caveat, vagal activation does not have uniformly favourable effects in all types of cancer metastasis, notably prostate cancer whereby muscarinic stimulation actually favours tumor invasion [1]. Specific situations in which sensory, vagal or neuroimmune pathways may need to be defined. Could there be a role for neurostimulation or neuromodulation of TRPV1 expressing sensory nerves in limiting metastasis? Do vagal nuclei or the central nervous system have systemic effects? A role for psychosocial stresses and resulting neuroendocrine effects on cancer mortality are mentioned in particular [1]. Interestingly, by acting on central neurotransmission, VNS is an established therapy in severe depression and may thus attenuate these unfavourable neuroendocrine effects [4].

Taken together, a role for VNS as a novel neuroimmunomodulation therapy in cancer is suggested. VNS has widespread systemic epigenetic and immunological effects with presumptive anti-tumoral effects. Furthermore, owing to an anti-glutamate effect, VNS may have a role in the prevention of certain metastases to the brain and further research is warranted. Once again, Prof Dr Erin is congratulated on an important and thought-provoking paper.