Functional Network Pipeline Reveals Genetic Determinants Associated with in Situ Lymphocyte Proliferation and Survival of Cancer Patients
Functional Network Pipeline Reveals Genetic Determinants Associated with in Situ Lymphocyte Proliferation and Survival of Cancer Patients
复制标题
DOI：
10.1126/scitranslmed.3007240
复制
发表时间：
2014-03-19
影响因子：
17.1
通讯作者：
Galon, Jerome
中科院分区：
文献类型：
--
作者：
Mlecnik, Bernhard;Bindea, Gabriela;Galon, Jerome
肿瘤微环境是一个复杂的细胞因子网络的宿主，这些细胞因子有助于形成肿瘤内免疫反应。研究了结直肠癌中59种细胞因子和受体及其功能网络的染色体获得和丢失，以及表达分析。显示了13种细胞因子的局部表达变化。转移性患者表现出4号染色体细胞因子缺失频率增加。白细胞介素15（IL 15）缺失与IL 15表达降低、肿瘤复发风险升高和患者生存率降低相对应。IL 15表达降低影响局部B和T淋巴细胞的增殖。在浸润边缘和肿瘤中心有增殖性B和T细胞的患者无病生存期显著延长。这些结果描述了染色体不稳定性作为调节人类肿瘤中局部细胞因子表达的机制，并强调了IL 15的主要作用。我们的数据提供了导致肿瘤内特异性免疫细胞密度变化的进一步机制，以及局部活跃淋巴细胞增殖对患者生存的重要性。
The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.