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- Engineering immunotherapies for thyroid cancerPublication . Silva, Francisca Borges Dias Monteiro da; Tavares, Álvaro; Deckers, JeroenThyroid cancer affects millions of people worldwide, particularly women. While most thyroid cancer patients have a good long-term prognosis, advanced anaplastic thyroid cancer is one of the most aggressive human malignancies. For most patients suffering from anaplastic thyroid cancer, treatment options are severely limited as tumors are resistant to conventional treatments. Anaplastic thyroid cancers typically have a highly immunosuppressive, pro-tumorigenic phenotype, characterized by high levels of immune checkpoint expression and the accumulation of tumor-associated macrophages that can account for more than 50% of the tumor volume. These immune-mediated mechanisms that facilitate rapid tumor growth represent attractive new treatment opportunities, particularly combinations of immunotherapies targeting T-cells and macrophages. The concept of innate immune memory, also known as trained immunity, has recently gained significant attention in the study of the innate immune system. It has also been shown that the induction of trained immunity can help overcome immunosuppression and can be beneficial in the context of cancer. Given this fact, we proposed trained immunity as a therapy target to overcome the characteristic immunosuppressive environment of anaplastic thyroid cancer. The research was conducted to determine the best conditions for inducing trained immunity in bone marrow-derived macrophages. We focused on commonly used primary stimuli such as β-glucan, bacillus Calmette-Guérin (BCG) vaccine, and MDP and secondary bacterial stimuli. Furthermore, tumor culture medium was used as a secondary stimulus. Through measurements of cytokine production, we detected the induction of trained immunity in bone marrow-derived macrophages trained with BCG and we observed that factors released by tumor cells can have a comparable effect as bacterial stimuli. We also examined the effect of a tumor on the immune system, looking at the cytokine production of splenocytes and bone marrow-derived macrophages of tumor-bearing mice. At the same time, we analyzed immune cell populations of tumor-bearing mice using flow cytometry, focusing on myeloid, lymphoid, and progenitor cell populations. In summary, this study provides fundamental new knowledge on how to target the bone marrow and induce trained immunity as a new treatment paradigm for anaplastic thyroid cancer.