Jens Venema1, Margo Dona2, Marieke de Laat1, Heidi Lemmers1, Romana Netea-Maier1, Henri Timmers1
(1) Internal Medicine, Radboudumc, Nijmegen, The Netherlands.
(2) Faculty of Science, Institute of Biology Leiden, Animal sciences, Universiteit Leiden, Leiden, The Netherlands.
Introduction
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms arising from cells in the adrenal medulla or from extra-adrenal paraganglia. While the immunogenic nature of PPGL has been suggested in previous research, further understanding of how different tumor-related characteristics influence the immune system in patients with or at hereditary risk of PPGL is lacking.
Aim
To explore the impact of tumor presence, catecholamines, and germline mutations on the circulatory immune system in patients with PPGL.
Methods
Blood was collected during routine patient care from 20 patients with catecholamine-producing PPGL, 22 patients with biochemically negative PPGL, 18 asymptomatic carriers of pathogenic variants in PPGL susceptibility genes, and 20 healthy controls. All groups were age and sex matched. Immune cells were isolated, and the ex vivo cytokine production in response to various stimuli was assessed.
Results
All three patient groups, including asymptomatic carriers, showed decreased cytokine production compared to healthy controls. There were no significant differences between catecholamine-producing and biochemically negative PPGLs. Decreased IL-8 production was observed in patients with a noradrenergic tumor compared to biochemically negative tumors. Asymptomatic carriers with SDH-subunit mutations showed decreased IL-8 production compared to other germline mutations. Patients with metastatic disease showed increased production of the immunosuppressive cytokine IL-10 and increased lactate production upon stimulation.
Conclusion
While these results are indicative of an immunosuppressed state in all patients with (an increased risk of) PPGL, it appears that catecholamine excess itself has a modest effect. Normetanephrinergic phenotype, SDH-mutational status, and metastasis did show associations with specific cytokine responses.