Fiore Piera Filomena, Vacca Paola, Tumino Nicola, Besi Francesca, Pelosi Andrea, Munari Enrico, Marconi Marcella, Caruana Ignazio, Pistoia Vito, Moretta Lorenzo, Azzarone Bruno
Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
Cancers (Basel). 2021 Jan 9;13(2):224. doi: 10.3390/cancers13020224.
The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm's Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56/CD133) or an epithelial (CD56/CD133) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.
免疫反应在癌症生长和转移中起着至关重要的防御作用，是不同肿瘤中有前景的治疗靶点。免疫系统在常见的儿童肾恶性肿瘤——肾母细胞瘤（WT）中的作用仍有待探索。对WT免疫环境的特征分析有助于确定新的治疗策略，以针对可能的抑制机制和/或降低现有治疗的毒性。在本研究中，我们稳定了四种表达胚基（CD56/CD133）或上皮（CD56/CD133）表型的WT原代培养物，并研究了它们与天然免疫细胞（即NK细胞和单核细胞）的相互作用。我们发现细胞因子激活的NK细胞能有效杀伤WT细胞。然而，与WT原代细胞共培养后，NK细胞的细胞毒性活性受损，IFNγ产生减少，CD107a、DNAM-1和NKp30的表达降低。对WT细胞与单核细胞相互作用的影响分析表明，它们向交替激活的巨噬细胞（M2）极化，进而进一步损害NK细胞功能。总之，我们表明WT的胚基和上皮成分可能直接和间接促成肿瘤免疫抑制微环境，这可能在肿瘤进展中发挥作用。
