Objectives: Non-medullary thyroid cancer (NMTC) is the most common endocrine malignancy. Patients with advanced radioiodine refractory disease have poor prognosis and treatment options are limited, which is why new treatment modalities are warranted. In NMTC tumors, myeloid cells, such as tumor-associated macrophages, are abundant and have an immune tolerant pro-tumoral phenotype. Trained immunity describes a specific epigenetic and metabolic program in innate immune cells that leads to an increased proinflammatory phenotype. This mechanism might be used to reprogram myeloid cells and could be explored as a new treatment strategy for NMTC patients.

Methods: Peripheral blood was obtained from 26 NMTC patients and 7 healthy volunteers, bone marrow from 8 NMTC patients. Peripheral monocytes and stem cells were isolated and in these cells trained immunity was induced in vitro using different stimuli. Subsequently those cells differentiated into macrophages which were restimulated to evaluate cytokine production capacity. Additionally, macrophage polarization was assessed using flowcytometry.

Results: In peripheral blood derived monocytes, trained immunity could be induced with the stimuli β-glucan and interleukin-4 (IL-4), characterized by increased production of proinflammatory cytokines IL-6 and TNF after restimulation with either LPS or Pam3Cys. The fold increase of cytokine production was lower in NMTC patients than in healthy volunteers. Training of stem cells showed similar results, although less pronounced. Flowcytometry showed that β-glucan-, IL-1β- and IL-4-trained stem cells developed into macrophages with lower CD206 and higher CD86 expression, indicative of a more proinflammatory and anti-tumoral phenotype.

Conclusion: Reprogramming of myeloid progenitor cells in our trained immunity setting results in macrophages with an anti-tumoral phenotype. This underlines the reversibility of the functional programming of myeloid cells in thyroid cancer and indicates that trained immunity might be explored as a novel treatment strategy for patients with advanced NMTC.