Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
J Pathol. 2011 Feb;223(3):347-57. doi: 10.1002/path.2819. Epub 2010 Dec 10.
Ewing sarcoma is an aggressive round cell sarcoma with poor patient prognosis, particularly in cases of advanced-stage disease. Dynamic tumor-host immune interations within the tumor microenvironment may polarize in situ immune responses and shape tumor development and/or progression. To gain insight into the nature of tumour-host immune interactions within the Ewing sarcoma microenvironment, the presence and spatial distribution of infiltrating CD8(+) /CD4(+) T-lymphocytes were evaluated in therapy-naive Ewing sarcoma. Expression profiling of 40 different chemokines and several chemokine receptors was performed in therapy-naive tumours and cell lines by qPCR, immunohistochemistry, and flow cytometry. Considerable inter-tumour variation was observed regarding density, type, and distribution of infiltrating T-lymphocytes. Tumour-infiltrating T-cells contained significantly higher percentages of CD8(+) T-lymphocytes as compared to stroma-infiltrating cells, suggesting preferential migration of this T-cell type into tumour areas. Gene expression levels of several type 1-associated, pro-inflammatory chemokines (CXCR3- and CCR5-ligands CXCL9, CXCL10, and CCL5) correlated positively with infiltrating (CD8(+) ) T-lymphocyte numbers expressing corresponding chemokine receptors. Survival analyses demonstrated an impact of tumour-infiltrating, and not stroma-infiltrating, CD8(+) T-lymphocytes on tumour progression. At protein level, both tumour and stromal cells expressed the IFNγ-inducible chemokines CXCL9 and CXCL10. CCR5-ligand CCL5 was exclusively expressed by non-tumoural stromal/infiltrating cells. Together, our results indicate that an inflammatory immune microenvironment with high expression of type 1-associated chemokines may be critical for the recruitment of (CD8(+) ) T-lymphocytes expressing corresponding chemokine receptors. The observed impact of tumour-infiltrating (CD8(+) ) T-lymphocytes is consistent with a role for adaptive anti-tumour immunity in the prevention of Ewing sarcoma progression. Recognition of the merits and exploitation/induction of an inflammatory microenvironment may improve the efficacy of natural immune responses against, and (adoptive) immunotherapeutic approaches for, Ewing sarcoma.
尤因肉瘤是一种侵袭性圆形细胞肉瘤，患者预后较差，尤其是在晚期疾病中。肿瘤微环境中动态的肿瘤-宿主免疫相互作用可能会使原位免疫反应极化，并影响肿瘤的发展和/或进展。为了深入了解尤因肉瘤微环境中肿瘤-宿主免疫相互作用的性质，本研究评估了未经治疗的尤因肉瘤中浸润性 CD8(+) / CD4(+) T 淋巴细胞的存在和空间分布。通过 qPCR、免疫组织化学和流式细胞术，对未经治疗的肿瘤和细胞系中 40 种不同趋化因子和几种趋化因子受体的表达谱进行了分析。观察到浸润性 T 淋巴细胞的密度、类型和分布存在相当大的肿瘤间变异性。肿瘤浸润 T 细胞中 CD8(+) T 淋巴细胞的比例明显高于基质浸润细胞，提示这种 T 细胞类型优先迁移到肿瘤区域。几种 1 型相关的促炎趋化因子（CXCR3 和 CCR5 配体 CXCL9、CXCL10 和 CCL5）的基因表达水平与表达相应趋化因子受体的浸润性（CD8(+) ）T 淋巴细胞数量呈正相关。生存分析表明，肿瘤浸润而不是基质浸润的 CD8(+) T 淋巴细胞对肿瘤进展有影响。在蛋白质水平上，肿瘤细胞和基质细胞均表达 IFNγ 诱导的趋化因子 CXCL9 和 CXCL10。CCR5 配体 CCL5 仅由非肿瘤性基质/浸润细胞表达。总之，我们的研究结果表明，具有高表达 1 型相关趋化因子的炎症免疫微环境可能对表达相应趋化因子受体的（CD8(+) ）T 淋巴细胞的募集至关重要。观察到肿瘤浸润的（CD8(+) ）T 淋巴细胞的影响与适应性抗肿瘤免疫在预防尤因肉瘤进展中的作用一致。认识到炎症微环境的优点并加以利用/诱导可能会提高天然免疫反应对尤因肉瘤的疗效，以及（过继）免疫治疗方法。
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