ETA2024 Oral Presentations Oral Session 1: Topic Highlights (6 abstracts)
Reprogramming myeloid bone marrow progenitors in non-medullary thyroid cancer using trained immunity
Pepijn van Houten 1 , Martin Jaeger 2 , Liesbeth van Emst 3 , Prashant Changoer 4 , Willem Mulder 5 , Ilse van Engen-van Grunsven 6 , Manita Bremmers 7 , Sjoerd Franssen 7 , Han Bonenkamp 8 , Johannes de Wilt 8 , Willemijn Hobo 9 , Mihai Netea 3 & Romana Teodora Netea-Maier 10
1Radboud University Medical Center, Internal Medicine, Division of Endocrinology, Nijmegen, Netherlands; 2Radboudumc, Radboud University Nijmegen Medical, Internal Medicine, Nijmegen, Netherlands; 3Radboud University Medical Center, Department of Internal Medicine; 4Radboud University Medical Center, Department of Internal Medicine, Nijmegen, Netherlands; 5Radboudumc, Department of Internal Medicine; 6Radboud University Medical Center, Department of Pathology; 7Radboud University Medical Center, Department of Hematology; 8Radboud University Medical Center, Department of Surgery; 9Radboud University Medical Center, Department of Laboratory Medicine, Laboratory of Hematology; 10Radboud University Medical Centre, Department of Endocrinology, Nijmegen, Netherlands
Objective: The prognosis of patients with metastasized and radioactive iodine 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 for NMTC patients.
Methods: Peripheral blood and bone marrow were obtained from 36 NMTC patients with different NMTC histological forms (29 differentiated and 6 anaplastic NMTC) and 9 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 flowcytometry.
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 peripheral monocytes derived macrophages, trained immunity could be induced with the stimuli β-glucan and interleukin-4 (IL-4), characterized by an increased production of proinflammatory cytokines IL-6 and TNF after restimulation with either LPS or Pam3Cys. The fold change of increase of cytokine production was lower in NMTC patients than in healthy volunteers. Flowcytometry 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 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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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