OR17-04 Reprogramming myeloid bone marrow progenitors in non-medullary thyroid cancer using trained immunity

Abstract Disclosure: P. van Houten: None. M. Jaeger: None. P. Changoer: None. L. van Emst: None. W. Mulder: None. I.C. van Engen-van Grunsven: None. M. Bremmers: None. H.J. Bonenkamp: None. J.H. de Wilt: None. W. Hobo: None. M.G. Netea: None. R.T. Netea-Maier: None. Objectives: The prognosis of patients with metastasized and radioactive refractory non-medullary thyroid cancer (NMTC) is poor and treatment options are limited. In NMTC tumors, myeloid cells, such as tumor-associated macrophages, are abundant and have an immunosuppressive and pro-tumoral phenotype. Trained immunity describes a specific epigenetic and metabolic program in innate immune cells that leads to an increased proinflammatory phenotype. The aim of the present study is to assess whether this mechanism can be used to reprogram the myeloid cells, from different bodily compartments, from patients with NMTC and thus whether this could be explored as a new treatment strategy of NMTC patients. Methods: Peripheral blood and bone marrow were obtained from 50 NMTC patients with different NMTC histological forms (36 differentiated and 14 anaplastic NMTC) and 13 healthy volunteers. White blood cell counts and subtypes were measured in whole blood and compared between healthy controls and patients. Peripheral monocytes and CD34-positive bone marrow progenitors from bone marrow were isolated and in these cells trained immunity was induced ex vivo using different stimuli. Subsequently those cells differentiated into macrophages which were restimulated by TLR-agonists to measure cytokine production. Additionally, macrophage phenotype was assessed using flow cytometry. Results: White blood cell counts and percentages of different subtypes were comparable between healthy controls and patients with differentiated NMTC. However, compared to healthy controls and patients with differentiated NMTC, patients with anaplastic NMTC showed significantly higher white blood cell counts, with higher percentages of neutrophils and lower percentages of lymphocytes. In circulating monocytes, trained immunity could be induced with the stimuli β-glucan, BCG and interleukin-4 (IL-4), characterized by an increased production of proinflammatory cytokines IL-6 and TNF after restimulation with either LPS or Pam3Cys. Fold changes in increase in cytokine production after restimulation were comparable between healthy controls, patients with differentiated NMTC and patients with anaplastic NMTC. Flow cytometry showed that β-glucan-, IL-1β- and IL-4-trained stem cells developed into macrophages with lower CD206 and CD163 and higher CD86 expression, markers associated with a less immunosuppressive and more anti-tumoral phenotype. Conclusion: Using our ex vivo model, we show that reprogramming of myeloid progenitor cells from patients with NMTC in our trained immunity setting is possible. This results in macrophages with an increased proinflammatory cytokine production and differentiation towards an anti-tumoral phenotype. This suggests that trained immunity might be explored as a potential novel treatment strategy for patients with aggressive forms of NMTC. Presentation: Sunday, July 13, 2025