Department of Medicine, Division of Endocrinology, Diabetes and Metabolism and Center for Diabetes and Endocrine Research (CeDER), University of Toledo, College of Medicine and Life Sciences, 3000 Arlington Ave., M.S. 1186, Toledo, OH, 43614, USA.
J Immunother Cancer. 2019 Jan 7;7(1):3. doi: 10.1186/s40425-018-0483-y.
Thyroid cancer and thyroid autoimmunity are considered opposite extremes of immune-responses. However, several studies have suggested that thyroid cancer coexists with autoimmune thyroid diseases like Hashimoto Thyroiditis (HT) and Graves disease (GD). We have shown that the risk of developing thyroid cancer is higher in patients with a silent form of autoimmune thyroid disease -Euthyroid Hashimoto Thyroiditis-(EHT).
We analyzed data from 2633 consecutive patients with GD, HT, EHT and non-Autoimmune Thyroid Disease (Non-AITD) for the presence of Differentiated Thyroid Cancer (DTC). We further investigated the microenvironment, and cellular mechanism of protection from DTC in GD/EHT by ex-vivo aspirating infiltrates from thyroid samples. We also re-constituted in vitro the in-vivo microenvironment to mimic an in-vivo context. We isolated NK cells and differentiated macrophages into M1 and M2 phenotype from healthy human peripheral blood monocytes.
DTC was less frequent/aggressive in GD as compared to EHT or Non-AITD. Intra-thyroidal immune-cell profiling revealed differential Natural Killer (NK) cell activity and macrophage polarization in the settings of GD versus EHT. In GD, NK-cells were activated, and macrophages showed M1-like phenotype whereas, in EHT, NK-cells were less active and macrophages displayed M2-like phenotype. Furthermore, in vitro co-cultures of NK-cells with differentiated macrophage subsets revealed that the presence of activated NK (NA) cells favors M1 macrophages, boosts macrophage action and amplifies the innate defense mechanisms. Moreover, co-culture of M2 macrophages with NA, increases the cytotoxicity of NK-cells and favors a pro-inflammatory microenvironment that reverts the anti-inflammatory M2 towards pro-inflammatory M1.
Surveillance innate immune-cells like Natural Killer (NK) cells and macrophages are complementary to each other in their actions. We discovered here that activated NK-cells in the background of the thyroid autoimmune disease, GD, drive macrophage differentiation to the M1/killer phenotype which in turn is cytotoxic to cancer cells and down regulates the M2/repair phenotype. Understanding the molecular basis of macrophage-NK cell interface in Thyroid Cancer, ETH and GD will open new vistas for immunopathology and therapeutic intervention. Macrophages/innate immunity can be modulated from M2 to M1 phenotype to help treat thyroid cancer as naturally done by GD.
甲状腺癌和自身免疫性甲状腺疾病被认为是免疫反应的两个极端。然而，多项研究表明，甲状腺癌与自身免疫性甲状腺疾病（如桥本甲状腺炎[HT]和格雷夫斯病[GD]）并存。我们已经表明，在自身免疫性甲状腺疾病的沉默形式-甲状腺功能正常的桥本甲状腺炎（EHT）患者中，患甲状腺癌的风险更高。
我们分析了 2633 例连续 GD、HT、EHT 和非自身免疫性甲状腺疾病（非 AITD）患者的数据，以确定分化型甲状腺癌（DTC）的存在。我们通过从甲状腺样本中抽吸浸润物，进一步研究了 GD/EHT 中预防 DTC 的微环境和细胞机制。我们还在体外重建体内微环境，以模拟体内环境。我们从健康人外周血单核细胞中分离 NK 细胞，并将分化的巨噬细胞分化为 M1 和 M2 表型。
与 EHT 或非 AITD 相比，GD 中 DTC 的频率/侵袭性较低。甲状腺内免疫细胞分析显示，GD 与 EHT 相比，自然杀伤（NK）细胞活性和巨噬细胞极化存在差异。在 GD 中，NK 细胞被激活，巨噬细胞呈现 M1 样表型，而在 EHT 中，NK 细胞活性较低，巨噬细胞呈现 M2 样表型。此外，NK 细胞与分化的巨噬细胞亚群的体外共培养显示，激活的 NK（NA）细胞的存在有利于 M1 巨噬细胞，增强巨噬细胞的作用，并放大先天防御机制。此外，M2 巨噬细胞与 NA 的共培养增加了 NK 细胞的细胞毒性，并有利于恢复炎症 M2 至促炎 M1 的促炎微环境。
监测先天免疫细胞，如自然杀伤（NK）细胞和巨噬细胞，在其作用上是互补的。我们在这里发现，GD 中甲状腺自身免疫疾病背景下的激活 NK 细胞驱动巨噬细胞分化为杀伤性 M1 表型，进而对癌细胞具有细胞毒性，并下调 M2/修复表型。了解甲状腺癌、ETH 和 GD 中巨噬细胞-NK 细胞界面的分子基础将为免疫病理学和治疗干预开辟新的视野。可以将巨噬细胞/先天免疫从 M2 表型调节为 M1 表型，以帮助治疗甲状腺癌，就像 GD 自然发生的那样。
