Dacheux Mélanie A, Norman Derek D, Shin Yoojin, Tigyi Gábor J, Lee Sue Chin
Department of Physiology, University of Tennessee Health Science Center Memphis, 3N. Dunlap Street, Memphis, TN 38163, USA.
iScience. 2024 Sep 17;27(10):110971. doi: 10.1016/j.isci.2024.110971. eCollection 2024 Oct 18.
Autotaxin (ATX) is a lysophospholipase D that generates lysophosphatidic acid (LPA) and regulates cancer metastasis, therapeutic resistance, and tumor immunity. We found that myeloid cells in human melanoma biopsies abundantly express ATX and investigated its role in modulating innate tumor immunity using two models of melanoma metastasis-spontaneous and experimental. Targeted knockout of ATX in LysM+ myeloid cells in mice (LysM-KO) reduced both spontaneous and experimental B16-F10 melanoma metastases by ≥ 50%. Immunoprofiling revealed differences in M2-like alveolar macrophages, neutrophils and regulatory T cells in the metastatic lungs of LysM-WT versus LysM-KO that are model-dependent. These differences extend systemically, with LysM-KO mice bearing experimental metastasis having fewer neutrophils in the spleen than LysM-WT mice. Our results show that (1) LysM+ myeloid cells are an important source of ATX/LPA that promote melanoma metastasis by altering innate tumor immunity, and (2) intratumor and systemic immune profiles vary dynamically during disease progression and are model-dependent.
自分泌运动因子（ATX）是一种溶血磷脂酶D，可生成溶血磷脂酸（LPA），并调节癌症转移、治疗抗性和肿瘤免疫。我们发现，人类黑色素瘤活检组织中的髓样细胞大量表达ATX，并使用两种黑色素瘤转移模型——自发转移模型和实验转移模型，研究了其在调节先天性肿瘤免疫中的作用。在小鼠的LysM+髓样细胞中靶向敲除ATX（LysM-KO）可使自发和实验性B16-F10黑色素瘤转移减少≥50%。免疫分析显示，LysM-WT与LysM-KO转移性肺组织中M2样肺泡巨噬细胞、中性粒细胞和调节性T细胞存在差异，且这些差异取决于模型。这些差异具有全身性，携带实验性转移瘤的LysM-KO小鼠脾脏中的中性粒细胞比LysM-WT小鼠少。我们的结果表明：（1）LysM+髓样细胞是ATX/LPA的重要来源，通过改变先天性肿瘤免疫促进黑色素瘤转移；（2）在疾病进展过程中，肿瘤内和全身免疫谱会动态变化，且取决于模型。
