Induction of trained immunity in myeloid cells and their progenitors from thyroid cancer patients

Pepijn van Houten^1*Prashant Changoer¹Liesbeth van Emst¹Han J. Bonenkamp²Johannes H.W. de Wilt²Willemijn Hobo³Manita E.J. Bremmers⁴Mieke W.H. Roeven⁴Janneke Walraven⁵Petronella B. Ottevanger⁵Willem J.M. Mulder^6,7Mihai Netea^7,8Martin Jaeger¹Romana T. Netea-Maier^1,9

• ¹Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands, Nijmegen, Netherlands
• ²Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands, Nijmegen, Netherlands
• ³Departof of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands, Nijmegen, Netherlands
• ⁴Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands, Nijmegen, Netherlands
• ⁵Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands, Nijmegen, Netherlands
• ⁶Laboratory of Chemical Biology, Technische Universiteit Eindhoven, Eindhoven, Netherlands
• ⁷Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands, Nijmegen, Netherlands
• ⁸Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
• ⁹Research Center for Functional Genomics, Biomedicine and Translation Medicine, Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-Napoca, Romania

Background: The prognosis of patients with cancer in which tumor-associated macrophages with a pro-tumoral phenotype are abundant is poor. This includes aggressive forms of non-medullary thyroid carcinoma (NMTC). Trained immunity describes long-term epigenetic and metabolic reprogramming in innate immune cells and their bone marrow progenitors leading to improved responsiveness, which is currently being explored as a potential new treatment approach in cancer. We aimed to assess whether trained immunity can be induced in myeloid cells of patients with NMTC to enhance the anti-tumor immune response, and whether this effect is tumor specific or can be elicited in other forms of cancers sharing the immune-mediated pathophysiology, such as colorectal carcinoma (CRC). Methods: Peripheral blood and bone marrow were obtained from 53 NMTC patients (39 differentiated and 14 poorly differentiated/anaplastic NMTC), and 13 healthy controls. Peripheral monocytes and bone marrow progenitors were isolated ex vivo and trained immunity was induced using different stimuli. Cytokine production upon restimulation and expression of cell membrane activation markers were used as biomarkers of cellular activation. In addition, trained immunity was assessed in peripheral monocytes from seven CRC patients. Results: Training of circulating monocytes with β-glucan or interleukin-4 resulted in amplified cytokine production upon restimulation, a hallmark of trained immunity responses. Fold changes of increase in cytokine production were comparable between the NMTC subtypes, CRC and healthy controls. Flow cytometry showed that training of bone marrow progenitors resulted in macrophages with lower CD206 and CD163 and higher CD86 expression, a profile associated with a less immunosuppressive and more anti-tumoral phenotype. Conclusion: Ex vivo training of monocytes and bone marrow progenitors from patients with NMTC and CRC results in macrophages with increased proinflammatory cytokine production and differentiation towards an anti-tumoral phenotype. This suggests that trained immunity might be exploited as a potential novel treatment strategy for of cancer.