Pepijn van Houten1, Prashant Changoer2, Martin Jaeger2, Liesbeth van Emst2, Mihai Netea3, Han Bonenkamp4, Johannes de Wilt4, Petronella Ottevanger5, Janneke Walraven5, Romana Netea-Maier6
(1) Radboudumc, department of Internal Medicine, division of Endocrinology, Nijmegen, the Netherlands. (2) Radboudumc, department of Internal Medicine, division of Endocrinology, Nijmegen, the Netherlands. (3) Radboudumc, department of Internal Medicine, division of Infectious Diseases, Nijmegen, the Netherlands. (4) Radboudumc, department of Surgery, Nijmegen, the Netherlands. (5) Radboudumc, department of Medical Oncology, Nijmegen, the Netherlands. (6) Radboudumc, department of Internal Medicine, division of Endocrinology, Nijmegen, Netherlands.
Objectives:
Anaplastic thyroid cancer (ATC) is the most aggressive tumor with no curative treatment options. The ATC tumor-microenvironment is characterized by pro-tumoral immune cells but circulating immune cells of ATC patients have not yet been immunophenotyped. Here, we aim to compare the subset counts and functional phenotype of circulating immune cells in patients with ATC, other subtypes of TC and healthy controls, to provide new pathogenetic insights in search for therapeutic targets.
Methods:
Patients with ATC (n=11), poorly differentiated thyroid cancer (PDTC, n=9), differentiated thyroid cancer (DTC, n=22) and healthy controls (n=13) donated blood. Individuals with inflammatory or infectious comorbidities were excluded. Circulating immune cell counts were assessed. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for 24h and 7 days with different stimuli to assess cytokine production capacity by ELISA. Circulating inflammatory proteins were assessed in plasma by OLINK proteomics.
Results:
Circulating absolute numbers of neutrophils and monocytes were higher in ATC patients than in the other subgroups. After 7 days of PBMC stimulation, lymphocytes of ATC patients produced less interferon-γ and interleukin- (IL)-22 than the other subgroups. In contrast, 24h of stimulation resulted in increased concentrations of monocyte-derived cytokines in the ATC subgroup. In plasma, IL-6, IL-1RA and granulocyte-colony stimulating factor were higher in the ATC group than in the other subgroups, which could explain the high number of neutrophils in the ATC group. In addition, IL-6 and IL-1RA were elevated in PDTC patients compared to DTC patients and healthy controls.
Conclusion:
PBMCs of ATC patients have a reduced capacity to produce lymphocyte-derived cytokines while this is increased for the monocyte-derived cytokines compared to other TC groups. Plasma concentrations of cytokines linked to myelopoiesis were higher in ATC patients, which could explain the high counts of circulating myeloid cells and reflect the aggressiveness of the disease.