Nodal metastasis in cervical cancer occurs in clearly delineated fields of immune suppression in the pelvic lymph catchment area.
Nodal metastasis in cervical cancer occurs in clearly delineated fields of immune suppression in the pelvic lymph catchment area.
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DOI：
10.18632/oncotarget.5398
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Jordanova ES
中科院分区：
文献类型：
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作者：
Heeren AM;de Boer E;Bleeker MC;Musters RJ;Buist MR;Kenter GG;de Gruijl TD;Jordanova ES
在宫颈癌中，高频率的调节性T细胞(Tregs)和免疫抑制的PD-L1+CD14+抗原提呈细胞主导着肿瘤阳性淋巴结(LN+)的微环境。目前尚不清楚这是否仅限于LN+或在转移之前，源自原发肿瘤并通过肿瘤引流淋巴(TDLN)扩散。为探讨宫颈肿瘤淋巴系统的免疫抑制作用，对5例宫颈癌患者(共9个LN+和74个肿瘤阴性淋巴结(LN-−))进行了FoxP3+Tregs、CD8+T细胞、HLADR+和PD-L1+髓系细胞的免疫组织化学分析。Tregs和PD-L1+细胞在转移瘤细胞周围形成免疫抑制警戒线。重要的是，虽然高HLADR+和PD-L1+细胞率与LN+密切相关，但在LN+和邻近的LN−中，与较远解剖位置的LN−相比，TREG水平升高和CD8+T细胞/TREG比值降低。这些数据表明，在解剖上共定位的TDLN中描绘的Treg相关免疫抑制区域通过创造转移的利基环境而促进转移。这可能对宫颈癌(手术)干预的决策有重要意义。未来的努力应该包括实施免疫治疗方案来克服这种免疫抑制，建立局部区域控制和阻止全身肿瘤扩散。
In cervical cancer, high frequencies of regulatory T cells (Tregs) and immunosuppressive PD-L1+CD14+ antigen-presenting cells dominate the microenvironment of tumor-positive lymph nodes (LN+). It is unknown whether this is restricted to LN+ or precedes metastasis, emanating from the primary tumor and spreading through tumor-draining lymph nodes (TDLNs). To investigate immunosuppression in the lymphatic basin of cervical tumors, all dissected TDLNs of five cervical cancer patients (in total 9 LN+ and 74 tumor-negative lymph nodes (LN−)) were analyzed for FoxP3+ Tregs, CD8+ T cells, HLA-DR+- and PD-L1+ myeloid cells by immunohistochemistry. Tregs and PD-L1+ cells were found to form an immunosuppressive cordon around metastatic tumor cells. Importantly, whereas high HLA-DR+- and PD-L1+ cell rates were strongly associated with LN+, elevated Treg levels and decreased CD8+ T cell/Treg ratios were found similar in LN+ and adjacent LN−, as compared to LN− at more distant anatomical localizations. These data suggest that delineated fields of Treg-associated immune suppression in anatomically co-localized TDLNs enable metastasis by creating metastatic niches. This may be of importance for decision-making regarding (surgical) intervention in cervical cancer. Future efforts should include the implementation of immunotherapeutic regimens to overcome this immune suppression, establish loco-regional control and halt systemic tumor spread.