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Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth.

ABSTRACT: The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8⁺ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8⁺ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.

SUBMITTER: Reijmen E

PROVIDER: S-EPMC8671299 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction Tinnitus can become a strong stressor for some individuals, leading to imbalance of the autonomous nervous system with reduction of parasympathetic activity. It can manifest itself as sleep disturbances, anxiety and even depression. This condition can be reversed by bioelectrical vagal nerve stimulation (VNS). Conventional invasive VNS is an approved treatment for epilepsy and depression. Transcutaneous VNS (taVNS) stimulating the auricular branch of the vagus nerve has been shown to activate the vagal pathways similarly as an implanted VNS. Therefore, taVNS might also be a therapeutic alternative in health conditions such as tinnitus-related mental stress (TRMS). This retrospective study in 171 TRMS patients reports the clinical features, psychophysiological characteristics, and results of the heart rate variability (HRV) tests before and after test-taVNS. This study also reports the therapy outcomes of 113 TRMS patients treated with taVNS, in combination with standard tinnitus therapy. Methods Diagnostic tinnitus and hearing profiles were defined. To detect possible cardiac adverse effects, test-taVNS with heart rate monitoring as well as pre- and post-stimulation HRV tests were performed. Daily taVNS home therapy was prescribed thereafter. To assess therapeutic usefulness of taVNS, 1-year follow-up outcome was studied. Results of HRV tests were retrospectively analyzed and correlated to diagnostic data. Results The large majority of patients with TRMS suffer from associated symptoms such as sleep disturbances and anxiety. Baseline HRV data showed that more than three quarters of the 171 patients had increased sympathetic activity before test-taVNS. Test-taVNS shifted mean values of different HRV parameters toward increased parasympathetic activity in about 80% of patients. Test-taVNS did not cause any cardiac or other side effects. No significant adverse effects were reported in follow-up questionnaires. Conclusion TRMS is an example of a stress condition in which patients may benefit from taVNS. As revealed by HRV, test-taVNS improved parasympathetic function, most efficiently in patients with a low starting HRV level. Our tinnitus treatment program, including taVNS, effectively alleviated tinnitus stress and handicap. For wider clinical use, there is a great need for more knowledge about the optimal methodology and parameters of taVNS.

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Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth.

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