The Lack of Epithelial Interleukin-7 and BAFF/BLyS Gene Expression in Prostate Cancer as a Possible Mechanism of Tumor Escape from Immunosurveillance
The Lack of Epithelial Interleukin-7 and BAFF/BLyS Gene Expression in Prostate Cancer as a Possible Mechanism of Tumor Escape from Immunosurveillance
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DOI：
10.1158/1078-0432.ccr-08-1951
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发表时间：
2009-05-01
影响因子：
11.5
通讯作者：
Sorrentino, Carlo
中科院分区：
文献类型：
--
作者：
Di Carlo, Emma;D'Antuono, Tommaso;Sorrentino, Carlo
目的：人类前列腺具有上皮内和间质淋巴细胞，可形成淋巴滤泡(LF)，引起局部免疫反应。我们试图探讨T细胞和B细胞的两种基本生存因子IL-7和BAFF/BLyS在正常前列腺和肿瘤组织中是否表达，并影响前列腺内淋巴细胞的稳态。实验设计：我们使用实时逆转录-聚合酶链式反应和共聚焦显微镜检测细胞因子的产生，结合免疫组织化学来表征前列腺内淋巴细胞。结果：前列腺上皮细胞产生IL-7，BAFF/BLyS的比例较小。事实上，我们发现IL-7受体α表达于上皮内T淋巴细胞和滤泡旁T细胞，而BAFF-R表达于LFS的腺周B淋巴细胞和外套带B细胞。前列腺归巢的B和T淋巴细胞几乎没有增殖，而大多数表达抗凋亡蛋白bcl2，在末端脱氧核苷酸转移酶介导的dUTP缺口末端标记实验中显示出低的凋亡指数。前列腺癌(PCa)从正常腺体向肿瘤性腺体的转变以IL-7和BAFF/BLyS的产生显著下降为标志。因此，PCa的特点是上皮内淋巴细胞显著减少，LFS丢失。BCL-2的B细胞和T细胞表达减少，而凋亡事件增加。其余的前列腺癌浸润性淋巴细胞多为CD8(+)T细胞，缺乏终末分化，几乎不能穿透肿瘤腺体。结论：上皮IL-7和BAFF/BLyS的产生支持了前列腺癌内淋巴细胞的存活。它在前列腺癌中的丢失与前列腺癌相关淋巴细胞的严重枯竭有关，并指向一种新的肿瘤逃逸机制。
Purpose: The human prostate is endowed with intraepithelial and stromal lymphocytes, which may develop lymphoid follicles (LF) and allow a local immune response. We sought to investigate whether interleukin (IL)-7 and BAFF/BLyS, two fundamental survival factors for T and B cells, are expressed in the normal and neoplastic prostate and affect intraprostatic lymphocyte homeostasis.Experimental Design: We have used real-time reverse transcription-PCR of microdissected prostatic glands and confocal microscopy to detect cytokine production, combined with immunohistochemistry to characterize intraprostatic lymphocytes.Results: Prostatic epithelia constitutively produce IL-7 and, to a lesser extent, BAFF/BLyS. Indeed, we show that IL-7 receptor alpha is expressed by intraepithelial T lymphocytes and parafollicular T cells, whereas BAFF-R is found on periglandular B lymphocytes and mantle zone B cells of LFs. Prostate-homing B and T lymphocytes are scarcely proliferating, whereas most of them express the antiapoptotic protein bcl-2 and reveal a low apoptotic index in the terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling assay. The transition from normal to neoplastic glands in prostate cancer (PCa) is marked by a dramatic decline of IL-7 and BAFF/BLyS production. Accordingly, PCa is characterized by a significant reduction of intraepithelial lymphocytes and loss of LFs. B-cell and T-cell expression of bcl-2 decrease, whereas the apoptotic events increase. The remaining PCa-infiltrating lymphocytes are mostly CD8(+) T cells that lack terminal differentiation and barely penetrate neoplastic glands.Conclusions: These results suggest that epithelial IL-7 and BAFF/BLyS production support intraprostatic lymphocyte survival. Its loss in PCa is associated with a severe depletion of prostate-associated lymphocytes and points to a novel tumor escape mechanism.